Methods and compositions for treating schizophrenia

ABSTRACT

The invention relates to methods and compositions for treating schizophrenia or bipolar disorder (in particular, mania) by using a combination of a synaptic vesicle protein 2A (SV2A) inhibitor and an antipsychotic or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs thereof. In some embodiments, the methods and the compositions are for treating one or more positive and/or negative symptoms, as well as cognitive impairment, associated with schizophrenia or bipolar disorder (in particular, mania).

This application is a continuation of U.S. patent application Ser. No.14/080,531, filed Nov. 14, 2013 (pending), which claims priority andbenefit from U.S. Provisional Patent Application 61/726,440, filed Nov.14, 2012 (expired), the contents and disclosures of which areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The invention relates to methods and compositions for treatingschizophrenia or bipolar disorder (in particular, mania). In particular,it relates to the use of a combination of a synaptic vesicle protein 2A(SV2A) inhibitor and an antipsychotic in treating a subject having or atrisk for schizophrenia or bipolar disorder (in particular, mania).

BACKGROUND OF THE INVENTION

Schizophrenia is a chronic psychiatric disorder, characterized by a widespectrum of psychopathology, including positive symptoms such asaberrant or distorted mental representations (e.g., hallucinations,delusions), negative symptoms characterized by diminution of motivationand adaptive goal-directed action (e.g., anhedonia, affectiveflattening, avolition), and cognitive impairment. While abnormalities inthe brain are proposed to underlie the full spectrum of psychopathologyin schizophrenia, currently available antipsychotics are largelyineffective in treating cognitive impairments in schizophrenia patients.

Cognitive impairments in schizophrenia involve both frontal and temporallobe functions that include memory, attention, processing speed, andexecutive control. Recent observations, drawn from preclinical animalmodels and human neuroimaging studies, indicate that altered brainactivity/excitability in the medial temporal lobe memory system maycontribute to cognitive impairment and may also play a role inaugmenting psychotic symptoms due to disinhibition of dopaminergicneurons.

Cognitive deficits are increasingly recognized as a key clinical featurethat can be detected in a prodromal phase and in remission, as well asduring full expression of the illness but are not effectively treated byavailable antipsychotics.

Because untreated features of schizophrenia, especially impairedcognition, predict long-term disability in patients (Green et al.,Schizophr. Res. 2004, 72, 41-45), it is critical to develop effectivetherapies for the spectrum of this illness.

SUMMARY OF THE INVENTION

In accordance with a first aspect of the present invention, there isprovided a method for treating a subject suffering from schizophrenia orbipolar disorder (in particular, mania), or at risk thereof, the methodcomprising the step of administering to said subject a therapeuticallyeffective amount of a SV2A inhibitor or a pharmaceutically acceptablesalt, hydrate, solvate, or polymorph thereof in combination with atherapeutically effective amount of an antipsychotic or apharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof. In some embodiments, the methods of the present invention treatone or more positive and/or negative symptoms, as well as cognitiveimpairment, associated with schizophrenia. In some embodiments, themethods of the present invention treat one or more symptoms, as well ascognitive impairment, associated with bipolar disorder (in particular,mania). In some embodiments of this invention, the methods of thisinvention prevent or slow the progression of cognitive impairment orbipolar disorder (in particular, mania) of schizophrenia in saidsubject.

The SV2A inhibitor or a pharmaceutically acceptable salt, hydrate,solvate or polymorph thereof that is useful in the methods andcompositions of this aspect of the invention include those disclosed in,for example, United States U.S. patent application Ser. No. 12/580,464,International Patent Application PCT/US2009/005647, U.S. PatentApplication 61/105,847, U.S. Patent Application 61/152,631, and U.S.Patent Application 61/175,536. However, any SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate or polymorph thereofmay be used in the methods and compositions of this aspect of theinvention. In other embodiments, the SV2A inhibitor is selected from thegroup of SV2A inhibitors referred to in International PatentApplications WO2010/144712; WO2010/002869; WO2008/132139; WO2007/065595;WO2006/128693; WO2006/128692; WO2005/054188; WO2004/087658;WO2002/094787; WO2001/062726; U.S. Pat. Nos. 7,465,549; 7,244,747;5,334,720; 4,696,943; 4,696,942; U.S. Patent Application PublicationNumbers 20090312333; 20090018148; 20080081832; 2006258704; and UK PatentNumbers 1,039,113; and 1,309,692 or their pharmaceutically acceptablesalts, hydrates, solvates, or polymorphs. In other embodiments, the SV2Ainhibitor is selected from the group consisting of levetiracetam,brivaracetam, and seletracetam or derivatives or analogs orpharmaceutically acceptable salts, hydrates, solvates, or polymorphsthereof. In other embodiments, the SV2A inhibitor is levetiracetam or aderivative or an analog or a pharmaceutically acceptable salt, hydrate,solvate, or polymorph thereof. In other embodiments, the SV2A inhibitoris brivaracetam or a derivative or an analog or a pharmaceuticallyacceptable salt, hydrate, solvate, or polymorph thereof. In otherembodiments, the SV2A inhibitor is seletracetam or a derivative or ananalog or a pharmaceutically acceptable salt, hydrate, solvate, orpolymorph thereof.

The antipsychotic or a pharmaceutically acceptable salt, hydrate,solvate or polymorph thereof that is useful in the methods andcompositions of this invention include both typical and atypicalantipsychotics.

In some embodiments, the antipsychotics suitable for use in the presentinvention are selected from atypical antipsychotics, including, but notlimited to, those disclosed in, for example, U.S. Pat. Nos. 4,734,416;5,006,528; 4,145,434; 5,763,476; 3,539,573; 5,229,382; 5,532,372;4,879,288; 4,804,663; 4,710,500; 4,831,031; and 5,312,925, and EPPatents EP402644 and EP368388, and the pharmaceutically acceptablesalts, hydrates, solvates, and polymorphs thereof.

In some embodiments, atypical antipsychotics suitable for use in thepresent invention include, but are not limited to, aripiprazole,asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone,quetiapine, risperidone and ziprasidone, and the pharmaceuticallyacceptable salts, hydrates, solvates, and polymorphs thereof. In someembodiments, the antipsychotic of this invention is selected fromaripiprazole (Bristol-Myers Squibb), olanzapine (Lilly) and ziprasidone(Pfizer), and the pharmaceutically acceptable salts, hydrates, solvates,and polymorphs thereof.

In some embodiments, the antipsychotics suitable for use in the presentinvention are typical antipsychotics, including, but not limited to,acepromazine, benperidol, bromazepam, bromperidol, chlorpromazine,chlorprothixene, clotiapine, cyamemazine, diazepam, dixyrazine,droperidol, flupentixol, fluphenazine, fluspirilene, haloperidol,heptaminol, isopropamide iodide, levomepromazine, levosulpiride,loxapine, melperone, mesoridazine, molindone, oxypertine, oxyprothepine,penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone,pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl,pyridoxine, sulpiride, sultopride, tetrabenazine, thioproperazine,thioridazine, tiapride, tiotixene, trifluoperazine, triflupromazine,trihexyphenidyl, and zuclopenthixol, and the pharmaceutically acceptablesalts, hydrates, solvates, and polymorphs thereof.

In some embodiments of the present invention, the antipsychotic or apharmaceutically acceptable salt, hydrate, solvate or polymorph thereofmay be selected from compounds that are dopaminergic agents (such asdopamine D1 receptor antagonists or agonists, dopamine D₂ receptorantagonists or partial agonists, dopamine D3 receptor antagonists orpartial agonists, dopamine D4 receptor antagonists), glutamatergicagents, N-methyl-D-aspartate (NMDA) receptor positive allostericmodulators, glycine reuptake inhibitors, glutamate reuptake inhibitor,metabotropic glutamate receptors (mGluRs) agonists or positiveallosteric modulators (PAMs) (e.g., mGluR2/3 agonists or PAMs),glutamate receptor glur5 positive allosteric modulators (PAMs), M1muscarinic acetylcholine receptor (mAChR) positive allosteric modulators(PAMs), histamine H3 receptor antagonists,α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainatereceptor antagonists, ampakines (CX-516), glutathione prodrugs,noradrenergic agents (such as alpha-2 adrenergic receptor agonists orantagonists and catechol-O-methyl transferase (COMT) inhibitors),serotonin receptor modulators (such as 5-HT_(2A) receptor antagonists,5-HT_(1A) receptor partial agonists, 5-HT_(2c) agonists, and 5-HT6antagonists), cholinergic agents (such as alpha-7 nicotinic receptoragonists, alpha4-beta2 nicotinic receptor agonists, allostericmodulators of nicotinic receptors and acetylcholinesterase inhibitors,muscarinic receptor agonists and antagonists), cannabinoid CB1antagonists, neurokinin 3 antagonists, neurotensin agonists, monoamineoxidase (MAO) B inhibitors, PDE10 inhibitors, neuronal nitric oxidesynthase (nNOS) inhibitors, neurosteroids, and neurotrophic factors.

In some embodiments, the antipsychotic or a pharmaceutically acceptablesalt, hydrate, solvate or polymorph thereof that is useful in themethods and compositions of this invention include compounds that may beused to treat at least one sign or symptom of schizophrenia or bipolardisorder (in particular, mania).

In some embodiments of this aspect of the invention, the antipsychoticis administered at a dose that is subtherapeutic as compared to the doseat which it is therapeutically effective when administered in theabsence of the SV2A inhibitor.

In some embodiments of the invention, the SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate or polymorph thereofcan be administered at doses as disclosed, for example, in U.S. patentapplication Ser. No. 12/580,464, International Patent ApplicationPCT/US2009/005647, U.S. Patent Application 61/105,847, U.S. PatentApplication 61/152,631, U.S. Patent Application 61/175,536, and U.S.Patent Application 61/441,251. In other embodiments of the invention,the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate,solvate or polymorph thereof is administered every 12 or 24 hours at adaily dose of about 0.001 mg/kg to 5 mg/kg. In other embodiments of theinvention, the SV2A inhibitor or a pharmaceutically acceptable salt,hydrate, solvate or polymorph thereof is administered every 12 or 24hours at a daily dose of about 0.1 to 5 mg/kg, or about 1 to 2 mg/kg, orabout 0.1 to 0.2 mg/kg, or about 0.01 to 2.5 mg/kg, or about 0.1 to 2.5mg/kg, or about 0.4 to 2.5 mg/kg, or about 0.6 to 1.8 mg/kg, or about0.04 to 2.5 mg/kg, or about 0.06 to 1.8 mg/kg, or about 0.01 to 1 mg/kg,or about 0.001 to 1 mg/kg, or about 0.5 mg/kg to 5 mg/kg, or about 0.05mg/kg to 0.5 mg/kg. In other embodiments of this aspect of theinvention, the SV2A inhibitor or a pharmaceutically acceptable salt,hydrate, solvate or polymorph thereof is administered every 12 or 24hours at a daily dose of about 0.1 to 0.2 mg/kg, or about 0.01 to 2.5mg/kg, or about 0.1 to 2.5 mg/kg, or about 0.4 to 2.5 mg/kg, or about0.6 to 1.8 mg/kg, or about 0.04 to 2.5 mg/kg, or about 0.06 to 1.8mg/kg, or about 2.0 to 4.0 mg/kg, or about 2.0 to 3.0 mg/kg, or about3.0 to 4.0 mg/kg, or about 0.2 to 0.4 mg/kg, or about 0.2 to 0.3 mg/kg,or about 0.3 to 0.4 mg/kg, or about 0.001-5 mg/kg, or about 0.001-0.5mg/kg, or about 0.01-0.5 mg/kg. In some embodiments, the SV2A inhibitormay be selected from the group consisting of levetiracetam,brivaracetam, and seletracetam or derivatives or analogs orpharmaceutically acceptable salts, hydrates, solvates, or polymorphsthereof, said SV2A inhibitor being administered every 12 or 24 hours ata daily dose selected from any of the above.

In some embodiments of the invention, the SV2A inhibitor and theantipsychotic, or their pharmaceutically acceptable salts, hydrates,solvates or polymorphs are administered simultaneously, or sequentially,or in a single formulation, or in separate formulations packagedtogether. In other embodiments, the SV2A inhibitor and theantipsychotic, or their pharmaceutically acceptable salts, hydrates,solvates or polymorphs are administered via different routes. As usedherein, “combination” includes administration by any of theseformulations or routes of administration.

In some embodiments of the invention, the combined treatment has alonger or improved therapeutic effect in the subject than is attained byadministering the antipsychotic or a pharmaceutically acceptable salt,hydrate, solvate or polymorph thereof in the absence of the SV2Ainhibitor or a pharmaceutically acceptable salt, solvate, hydrate, orpolymorph thereof by at least about 1.5×, or 2.0×, or 2.5×, or 3.0×, or3.5×, or 4.0×, or 4.5×, or 5.0×, or 5.5×, or 6.0×, or 6.5×, or 7.0×, or7.5×, or 8.0×, or 8.5×, or 9.0×, or 9.5×, or 10×, or greater than about10×.

In some embodiments of the invention, the combined treatment has alonger or improved therapeutic effect in the subject than is attained byadministering the SV2A inhibitor or a pharmaceutically acceptable salt,hydrate, solvate or polymorph thereof in the absence of theantipsychotic or a pharmaceutically acceptable salt, solvate, hydrate,or polymorph thereof by at least about 1.5×, or 2.0×, or 2.5×, or 3.0×,or 3.5×, or 4.0×, or 4.5×, or 5.0×, or 5.5×, or 6.0×, or 6.5×, or 7.0×,or 7.5×, or 8.0×, or 8.5×, or 9.0×, or 9.5×, or 10×, or greater thanabout 10×.

In accordance with another aspect of the present invention, there isprovided a method of increasing the therapeutic index of anantipsychotic or a pharmaceutically acceptable salt, hydrate, solvate orpolymorph thereof in a method of treating schizophrenia or bipolardisorder (in particular, mania) in a subject in need or at risk thereof,comprising administering a SV2A inhibitor or a pharmaceuticallyacceptable salt, hydrate, solvate or polymorph thereof in combinationwith the antipsychotic or a pharmaceutically acceptable salt, hydrate,solvate or polymorph thereof to said subject.

In some embodiments, the increase in the therapeutic index of theantipsychotic or a pharmaceutically acceptable salt, hydrate, solvate orpolymorph thereof is greater than the therapeutic index of theantipsychotic or a pharmaceutically acceptable salt, hydrate, solvate orpolymorph thereof when administered in the absence of the SV2A inhibitoror a pharmaceutically acceptable salt, hydrate, solvate or polymorphthereof by at least about 1.5×, or 2.0×, or 2.5×, or 3.0×, or 3.5×, or4.0×, or 4.5×, or 5.0×, or 5.5×, or 6.0×, or 6.5×, or 7.0×, or 7.5×, or8.0×, or 8.5×, or 9.0×, or 9.5×, or 10×, or greater than about 10×.

In accordance with another aspect of this invention, there is provided apharmaceutical composition for treating a subject suffering fromschizophrenia or bipolar disorder (in particular, mania), or at riskthereof, the composition comprising a SV2A inhibitor and anantipsychotic or their pharmaceutically acceptable salts, hydrates,solvates or polymorphs thereof. In some embodiments, the composition ofthis invention is for treating one or more positive and/or negativesymptoms, as well as cognitive impairment, associated withschizophrenia. In some embodiments, the composition of this invention isfor treating one or more symptoms, as well as cognitive impairment,associated with bipolar disorder (in particular, mania). In someembodiments, the composition is in a liquid form. In some embodiments,the composition is in an aqueous solution. In some embodiments, thecomposition is in a suspension form. In some embodiments, thecomposition is in a sustained release form, or a controlled releaseform, or a delayed release form, or an extended release form. In someembodiments, the composition is in a unit dosage form. In otherembodiments, the two components of the compositions are in separatedelivery forms packaged together.

In some embodiments of this invention, the composition compriseslevetiracetam, brivaracetam, seletracetam, or a derivative or an analogor a pharmaceutically acceptable salt, hydrate, solvate or polymorphthereof and an antipsychotic or a derivative or an analog or apharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

In some embodiments of this invention, the SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate or polymorph thereofin the composition is present in an amount of 0.07-350 mg, or 50-250 mg,or 3-50 mg. In some embodiments, the SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate or polymorph thereofis present in an amount less than 350 mg, less than 250 mg, less than200 mg, less than 150 mg, less than 100 mg, less than 50 mg, less than10 mg, less than 5 mg, less than 1 mg, less than 0.5 mg, less than 0.1mg, or less than 0.07 mg. In certain embodiments of this aspect of theinvention, the SV2A inhibitor is present in an amount of 0.07-60 mg,0.07-350 mg, 25-60 mg, 25-125 mg, 50-250 mg, 5-140 mg, 0.7-180 mg,125-240 mg, 3-50 mg, or 3-60 mg. In other embodiments of this aspect ofthe invention, the SV2A inhibitor is present in an amount of 0.05-35 mg.In some embodiments of the composition of this invention, the SV2Ainhibitor may be selected from the group consisting of levetiracetam,brivaracetam, and seletracetam or derivatives or analogs orpharmaceutically acceptable salts, hydrates, solvates, or polymorphsthereof, said SV2A inhibitor being present in an amount selected fromany of the above.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts increased mRNA expression of the gene encoding SV2A inthe dentate gyrus of the hippocampus of aged-impaired rats (AI) ascompared to young rats (Y) and aged-unimpaired rats (AU). NormalizedAffymetrix GeneChip probe set signal values (Y-axis), as a measure ofmRNA expression, are plotted against learning indices of different rats,as a measure of cognitive impairment.

FIG. 2 depicts the effects of administering levetiracetam on the spatialmemory retention of six aged-impaired rats (AI) in a Morris Water Maze(MWM) test. Three treatment conditions were employed: vehicle control,levetiracetam (5 mg/kg/day) and levetiracetam (10 mg/kg/day). The AIrats were trained for two consecutive days, with a one-time treatmentprior to the training trials per day. 24 hours later, the AI rats weretested. The time the AI rats, 24 hours after treatment with thedifferent conditions and two days of training, spent swimming in thetarget quadrant or the target annulus in a memory retention trial isused as a measure of spatial memory retention. The target quadrantrefers to the quadrant of the maze (which is a circular pool) where theescape platform is placed during the training trials. The target annulusrefers to the exact location of the escape platform during the trainingtrials.

FIG. 3 depicts the effects of administering levetiracetam on the spatialmemory retention of ten aged-impaired rats (AI) in an eight-arm RadialArm Maze (RAM) test. Six treatment conditions were employed: vehiclecontrol, levetiracetam (1.25 mg/kg), levetiracetam (2.5 mg/kg),levetiracetam (5 mg/kg), levetiracetam (10 mg/kg) and levetiracetam (20mg/kg). In the RAM task used, there was a one-hour delay betweenpresentation of a subset of arms (5 arms available and 3 arms blocked)and completion of the eight-arm win-shift task (eight arms available).Rats were pre-treated 30-40 minutes before daily trials with a one-timedrug/control treatment. The number of errors made by the rats after thedelay was used as a measure of spatial memory retention. Errors weredefined as instances when rats entered an arm from which food hadalready been retrieved in the pre-delay component of the trial or whenrats re-visited an arm in the post-delay session that had already beenvisited. Paired t-tests were used to compare the number of errorsbetween different doses of levetiracetam and vehicle control.

FIG. 4 depicts the effects of administering levetiracetam or valproateseparately on the spatial memory retention of ten aged-impaired rats(AI) in an eight-arm Radial Arm Maze (RAM) test.

FIG. 5 depicts the effects of administering levetiracetam or valproatein combination on the spatial memory retention of ten aged-impaired rats(AI) in an eight-arm Radial Arm Maze (RAM) test.

FIG. 6 shows an isobologram plotting levetiracetam dose againstvalproate dose. The diagonal straight line is the line of additivity,anchored on each axis by the lowest effective doses of valproate andlevetiracetam when assessed individually.

FIG. 7 depicts the experimental design of the human trials forlevetiracetam treatment.

FIG. 8A depicts the average activity in the left CA3 of aMCI subjectswith placebo treatment and age-matched control subjects with placebotreatment during the presentation of lure stimuli that the subjectcorrectly identified as “similar.”

FIG. 8B depicts the average activity in the left CA3 of aMCI subjectswith placebo treatment or levetiracetam treatment (125 mg twice a dayfor two weeks) during the presentation of lure stimuli that the subjectcorrectly identified as “similar.”

FIG. 8C is a table of the data represented in FIGS. 8A and 8B.

FIG. 9A depicts the average activity in the left entorhinal cortex ofage-matched control subjects with placebo treatment and aMCI subjectswith placebo treatment during the presentation of lure stimuli that thesubject correctly identified as “similar.”

FIG. 9B depicts the average activity in the left entorhinal cortex ofthe same aMCI subjects with placebo treatment or levetiracetam treatment(125 mg twice a day for two weeks) during the presentation of lurestimuli that the subject correctly identified as “similar.”

FIG. 9C is a table of the data represented in FIGS. 9A and 9B.

FIG. 10A depicts an example of the sequence of images shown to subjectsin the explicit 3-alternative forced choice task described in Example 2.

FIG. 10B shows sample pairs of similar (“lure”) images.

FIG. 11 shows the difference between the aMCI (placebo) subjects andage-matched control (placebo) subjects in their performance of theexplicit 3-alternative forced choice task described in Example 2. Eachbar represents the proportion of the subject responses (old, similar, ornew) when presented with a lure image.

FIG. 12 shows the difference between the same aMCI subjects with placebotreatment or with levetiracetam treatment (125 mg twice a day for twoweeks) in their performance of the explicit 3-alternative forced choicetask described in Example 2. Each bar represents the proportion of thesubjects responses (old, similar, or new) when presented with a lureimage.

FIG. 13 is a table of the data represented in FIGS. 11 and 12.

FIG. 14A shows the difference between the age-matched control (placebo)subjects and the aMCI subjects treated with placebo or withlevetiracetam (125 mg twice a day for two weeks) in their performance ofthe Buschke Selective reminding Test—Delayed Recall.

FIG. 14B is a table of the data represented in FIG. 14A.

FIG. 15A shows the difference between the control (placebo) subjects andthe aMCI subjects treated with placebo or with levetiracetam (125 mgtwice a day for two weeks) in their performance of the Benton VisualRetention Test.

FIG. 15B is a table of the data represented in FIG. 15A.

FIG. 16A shows the difference between the control (placebo) subjects andthe aMCI subjects treated with placebo or with levetiracetam (125 mgtwice a day for two weeks) in their performance of the Verbal PairedAssociates Test—Recognition.

FIG. 16B is a table of the data represented in FIG. 16A.

FIG. 17A shows the difference between the control (placebo) subjects andthe aMCI subjects treated with placebo or with levetiracetam (125 mgtwice a day for two weeks) in their performance of the Verbal PairedAssociates Test—Delayed Recall.

FIG. 17B is a table of the data represented in FIG. 17A.

FIG. 18A is a table showing the subject selection process for the humanlevetiracetam trial described in Example 2.

FIG. 18B is a table showing the characteristics of the subjects selectedfor the human levetiracetam trial described in Example 2.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise defined herein, scientific and technical terms used inthis application shall have the meanings that are commonly understood bythose of ordinary skill in the art. Generally, nomenclature used inconnection with, and techniques of, cell and tissue culture, molecularbiology, cell and cancer biology, neurobiology, neurochemistry,virology, immunology, microbiology, pharmacology, genetics and proteinand nucleic acid chemistry, described herein, are those well known andcommonly used in the art.

The methods and techniques of the present invention are generallyperformed, unless otherwise indicated, according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout thisspecification. See, e.g. “Principles of Neural Science”, McGraw-HillMedical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”,Oxford University Press, Inc. (1995); Lodish et al., “Molecular CellBiology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths etal., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co.,N.Y. (1999); Gilbert et al., “Developmental Biology, 6th ed.”, SinauerAssociates, Inc., Sunderland, Mass. (2000).

Chemistry terms used herein are used according to conventional usage inthe art, as exemplified by “The McGraw-Hill Dictionary of ChemicalTerms”, Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985).

All of the above, and any other publications, patents and publishedpatent applications referred to in this application are specificallyincorporated by reference herein. In case of conflict, the presentspecification, including its specific definitions, will control.

Throughout this specification, the word “comprise” or variations such as“comprises” or “comprising” will be understood to imply the inclusion ofa stated integer (or components) or group of integers (or components),but not the exclusion of any other integer (or components) or group ofintegers (or components).

The singular forms “a,” “an,” and “the” include the plurals unless thecontext clearly dictates otherwise.

The term “including” is used to mean “including but not limited to”.“Including” and “including but not limited to” are used interchangeably.

The term “agent” is used herein to denote a chemical compound (such asan organic or inorganic compound, a mixture of chemical compounds), abiological macromolecule (such as a nucleic acid, an antibody, includingparts thereof as well as humanized, chimeric and human antibodies andmonoclonal antibodies, a protein or portion thereof, e.g., a peptide, alipid, a carbohydrate), or an extract made from biological materialssuch as bacteria, plants, fungi, or animal (particularly mammalian)cells or tissues. Agents include, for example, agents which are knownwith respect to structure, and those which are not known with respect tostructure.

A “patient”, “subject”, or “individual” are used interchangeably andrefer to either a human or a non-human animal. These terms includemammals, such as humans, primates, livestock animals (including bovines,porcines, etc.), companion animals (e.g., canines, felines, etc.) androdents (e.g., mice and rats).

“Cognitive function” or “cognitive status” refers to any higher orderintellectual brain process or brain state, respectively, involved inlearning and/or memory including, but not limited to, attention,information acquisition, information processing, working memory,short-term memory, long-term memory, anterograde memory, retrogradememory, memory retrieval, discrimination learning, decision-making,inhibitory response control, attentional set-shifting, delayedreinforcement learning, reversal learning, the temporal integration ofvoluntary behavior, expressing an interest in one's surroundings andself-care, speed of processing, reasoning and problem solving and socialcognition.

In humans, cognitive function may be measured, for example and withoutlimitation, by the clinical global impression of change scale(CIBIC-plus scale); the Mini Mental State Exam (MMSE); theNeuropsychiatric Inventory (NPI); the Clinical Dementia Rating Scale(CDR); the Cambridge Neuropsychological Test Automated Battery (CANTAB);the Sandoz Clinical Assessment-Geriatric (SCAG), the Buschke SelectiveReminding Test (Buschke and Fuld, 1974); the Verbal Paired Associatessubtest; the Logical Memory subtest; the Visual Reproduction subtest ofthe Wechsler Memory Scale-Revised (WMS-R) (Wechsler, 1997); the BentonVisual Retention Test, or the explicit 3-alternative forced choice task,or MATRICS consensus neuropsychological test battery. See Folstein etal., J Psychiatric Res 12: 189-98, (1975); Robbins et al., Dementia 5:266-81, (1994); Rey, L'examen clinique en psychologie, (1964); Kluger etal., J Geriatr Psychiatry Neurol 12:168-79, (1999); Marquis et al., 2002and Masur et al., 1994. Also see Buchanan, R. W., Keefe, R. S. E.,Umbricht, D., Green, M. F., Laughren, T., and Marder, S. R. (2011), TheFDA-NIMH-MATRICS guidelines for clinical trial design ofcognitive-enhancing drugs: what do we know 5 years later? Schizophr.Bull. 37, 1209-1217.

In animal model systems, cognitive function may be measured in variousconventional ways known in the art, including using a Morris Water Maze(MWM), Barnes circular maze, elevated radial arm maze, T maze or anyother mazes in which the animals use spatial information. Cognitivefunction can be assessed by reversal learning, extradimensional setshifting, conditional discrimination learning and assessments of rewardexpectancy. Other tests known in the art may also be used to assesscognitive function, such as novel object recognition and odorrecognition tasks.

Cognitive function may also be measured using imaging techniques such asPositron Emission Tomography (PET), functional magnetic resonanceimaging (fMRI), Single Photon Emission Computed Tomography (SPECT), orany other imaging technique that allows one to measure brain function.In animals, cognitive function may also be measured withelectrophysiological techniques.

“Promoting” cognitive function refers to affecting impaired cognitivefunction so that it more closely resembles the function of a normal,unimpaired subject. Cognitive function may be promoted to any detectabledegree, but in humans preferably is promoted sufficiently to allow animpaired subject to carry out daily activities of normal life at thesame level of proficiency as a normal, unimpaired subject.

“Preserving” cognitive function refers to affecting normal or impairedcognitive function such that it does not decline or does not fall belowthat observed in the subject upon first presentation or diagnosis, ordelays such decline.

“Improving” cognitive function includes promoting cognitive functionand/or preserving cognitive function in a subject.

“Cognitive impairment” refers to cognitive function in subjects that isnot as robust as that expected in a normal, unimpaired subject. In somecases, cognitive function is reduced by about 5%, about 10%, about 30%,or more, compared to cognitive function expected in a normal, unimpairedsubject. In other cases, “cognitive impairment” in subjects affected byschizophrenia or bipolar disorder (in particular, mania) refers tocognitive function in subjects that is not as robust as that expected innormal, unimpaired subject.

“Schizophrenia” refers to a chronic debilitating disorder, characterizedby a spectrum of psychopathology, including positive symptoms such asaberrant or distorted mental representations (e.g., hallucinations,delusions), negative symptoms characterized by diminution of motivationand adaptive goal-directed action (e.g., anhedonia, affectiveflattening, avolition), and cognitive impairment. While abnormalities inthe brain are proposed to underlie the full spectrum of psychopathologyin schizophrenia, currently available antipsychotics are largelyineffective in treating cognitive impairments in patients.

“Bipolar disorder” or “BP” or “manic depressive disorder” or “manicdepressive illness” refers to a chronic psychological/mood disorderwhich can be characterized by significant mood changes including periodsof depression and euphoric manic periods. BP may be diagnosed by askilled physician based on personal and medical history, interviewconsultation and physical examinations. The term “mania” or “manicperiods” or other variants refers to periods where an individualexhibits some or all of the following characteristics: racing thoughts,rapid speech, elevated levels of activity and agitation as well as aninflated sense of self-esteem, euphoria, poor judgment, insomnia,impaired concentration and aggression.

“Treating” a condition or patient refers to taking steps to obtainbeneficial or desired results, including clinical results. Beneficial ordesired clinical results include, but are not limited to, preventing orslowing the progression of the disease or disorder, or alleviation,amelioration, or slowing the progression, of one or more symptomsassociated with CNS disorders with cognitive impairment, such asschizophrenia or bipolar disorder (in particular, mania).

“Treating cognitive impairment” refers to taking steps to improvecognitive function in a subject with cognitive impairment so that thesubject's performance in one or more cognitive tests is improved to anydetectable degree, or is prevented from further decline. Preferably,that subject's cognitive function, after treatment of cognitiveimpairment, more closely resembles the function of a normal, unimpairedsubject. Treatment of cognitive impairment in humans may improvecognitive function to any detectable degree, but is preferably improvedsufficiently to allow the impaired subject to carry out daily activitiesof normal life at the same level of proficiency as a normal, unimpairedsubject. In some cases, “treating cognitive impairment” refers to takingsteps to improve cognitive function in a subject with cognitiveimpairment so that the subject's performance in one or more cognitivetests is improved to any detectable degree, or is prevented from furtherdecline. Preferably, that subject's cognitive function, after treatmentof cognitive impairment, more closely resembles the function of anormal, unimpaired subject. In some cases, “treating cognitiveimpairment” in a subject affecting by schizophrenia or bipolar disorder(in particular, mania) refers to takings steps to improve cognitivefunction in the subject so that the subject's cognitive function, aftertreatment of cognitive impairment, more closely resembles the functionof a normal, unimpaired subject.

“Administering” or “administration of” a substance, a compound or anagent to a subject can be carried out using one of a variety of methodsknown to those skilled in the art. For example, a compound or an agentcan be administered, intravenously, arterially, intradermally,intramuscularly, intraperitonealy, intravenously, subcutaneously,ocularly, sublingually, orally (by ingestion), intranasally (byinhalation), intraspinally, intracerebrally, and transdermally (byabsorption, e.g., through a skin duct). A compound or agent can alsoappropriately be introduced by rechargeable or biodegradable polymericdevices or other devices, e.g., patches and pumps, or formulations,which provide for the extended, slow, or controlled release of thecompound or agent. Administering can also be performed, for example,once, a plurality of times, and/or over one or more extended periods. Insome aspects, the administration includes both direct administration,including self-administration, and indirect administration, includingthe act of prescribing a drug. For example, as used herein, a physicianwho instructs a patient to self-administer a drug, or to have the drugadministered by another and/or who provides a patient with aprescription for a drug is administering the drug to the patient.

Appropriate methods of administering a substance, a compound or an agentto a subject will also depend, for example, on the age of the subject,whether the subject is active or inactive at the time of administering,whether the subject is cognitively impaired at the time ofadministering, the extent of the impairment, and the chemical andbiological properties of the compound or agent (e.g. solubility,digestibility, bioavailability, stability and toxicity). In someembodiments, a compound or an agent is administered orally, e.g., to asubject by ingestion, or intravenously, e.g., to a subject by injection.In some embodiments, the orally administered compound or agent is in anextended release or slow release formulation, or administered using adevice for such slow or extended release.

“SV2A inhibitor” refers to any agent, substance or compound that bindsto SV2A and reduces synaptic function by reducing pre-synaptic vesiclerelease (See, e.g., Noyer et al. 1995; Fuks et al. 2003; Lynch et al.2004; Gillard et al. 2006; Custer et al., 2006; Smedt et al., 2007; Yanget al., 2007; Meehan, “Levetiracetam has an activity-dependent effect oninhibitory transmission,” Epilepsia, 2012 Jan. 31; and Example 8 of WO2001/62726, all of which are specifically incorporated herein byreference.) A substance, or a compound or an agent is an SV2A inhibitoreven if it does not itself bind to SV2A, as long as it causes, oraffects the ability of, another compound or agent to bind SV2A or reducesynaptic function by reducing pre-synaptic vesicle release. SV2Ainhibitors, as used herein, include pharmaceutically acceptable salts ofthe inhibitors thereof. They also include hydrates, polymorphs,prodrugs, salts, and solvates of these inhibitors.

“Antipsychotic”, “antipsychotic agent”, “antipsychotic drug”, or“antipsychotic compound” refers to (1) a typical or an atypicalantipsychotic; (2) an agent that is selected from dopaminergic agents,glutamatergic agents, NMDA receptor positive allosteric modulators,glycine reuptake inhibitors, glutamate reuptake inhibitor, metabotropicglutamate receptors (mGluRs) agonists or positive allosteric modulators(PAMs) (e.g., mGluR2/3 agonists or PAMs), glutamate receptor glur5positive allosteric modulators (PAMs), M1 muscarinic acetylcholinereceptor (mAChR) positive allosteric modulators (PAMs), histamine H3receptor antagonists, AMPA/kainate receptor antagonists, ampakines(CX-516), glutathione prodrugs, noradrenergic agents, serotonin receptormodulators, cholinergic agents, cannabinoid CB1 antagonists, neurokinin3 antagonists, neurotensin agonists, MAO B inhibitors, PDE10 inhibitors,nNOS inhibits, neurosteroids, and neurotrophic factors; and/or (3) anagent that is useful in treating one or more signs or symptoms ofschizophrenia or bipolar disorder (in particular, mania).

“Typical antipsychotics”, as used herein, refer to conventionalantipsychotics, which produce antipsychotic effects as well as movementrelated adverse effects related to disturbances in the nigrostriataldopamine system. These extrapyramidal side effects (EPS) includeParkinsonism, akathisia, tardive dyskinesia and dystonia. SeeBaldessarini and Tarazi in Goodman & Gilman's The Pharmacological Basisof Therapeutics 10 Edition, 2001, pp. 485-520.

“Atypical antipsychotics”, as used herein, refer to antipsychotic drugsthat produce antipsychotic effects with little or no EPS and include,but are not limited to, aripiprazole, asenapine, clozapine, iloperidone,olanzapine, lurasidone, paliperidone, quetiapine, risperidone andziprasidone. “Atypical” antipsychotics differ from conventionalantipsychotics in their pharmacological profiles. While conventionalantipsychotics are characterized principally by D₂ dopamine receptorblockade, atypical antipsychotics show antagonist effects on multiplereceptors including the 5HT_(a) and 5HT_(c), serotonin receptors andvarying degrees of receptor affinities. Atypical antipsychotic drugs arecommonly referred to as serotonin/dopamine antagonists, reflecting theinfluential hypothesis that greater affinity for the 5HT₂ receptor thanfor the D₂, receptor underlies “atypical” antipsychotic drug action or“second generation” antipsychotic drugs. However, the atypicalantipsychotics often display side effects, including, but not limitedto, weight gain, diabetes (e.g., type II diabetes mellitus),hyperlipidemia, QTc interval prolongation, myocarditis, sexual sideeffects, extrapyramidal side effects and cataract. Thus, atypicalantipsychotics do not represent a homogeneous class, given theirdifferences in the context of both alleviation of clinical symptoms andtheir potential for inducing side effects such as the ones listed above.Further, the common side effects of the atypical antipsychotics asdescribed above often limit the antipsychotic doses that can be used forthese agents.

The term “simultaneous administration,” as used herein, means that theSV2A inhibitor and the antipsychotic, or their pharmaceuticallyacceptable salts, hydrates, solvates, or polymorphs, are administeredwith a time separation of no more than about 15 minutes, and in someembodiments no more than about 10 minutes. When the drugs areadministered simultaneously, the SV2A inhibitor and the antipsychotic,or their salts, hydrates, solvates, or polymorphs, may be contained inthe same dosage (e.g., a unit dosage form comprising both the SV2Ainhibitor and the antipsychotic) or in discrete dosages (e.g., the SV2Ainhibitor or its salt, hydrate, solvate, or polymorph is contained inone dosage form and the antipsychotic or its salt, hydrate, solvate, orpolymorph is contained in another dosage form).

The term “sequential administration” as used herein means that the SV2Ainhibitor and the antipsychotic, or their pharmaceutically acceptablesalts, hydrates, solvates, polymorphs, are administered with a timeseparation of more than about 15 minutes, and in some embodiments morethan about one hour, or up to 12-24 hours. Either the SV2A inhibitor orthe antipsychotic may be administered first. The SV2A inhibitor and theantipsychotic, or their salts, hydrates, solvents, or polymorphs, forsequential administration may be contained in discrete dosage forms,optionally contained in the same container or package.

A “therapeutically effective amount” of a drug or agent is an amount ofa drug or an agent that, when administered to a subject will have theintended therapeutic effect, e.g. improving cognitive function in asubject in a subject suffering from a disease or disorder (e.g.,schizophrenia or bipolar disorder (in particular, mania)), preventing orslowing the progression of a disease or disorder (e.g., schizophrenia orbipolar disorder (in particular, mania)), and/or alleviating,ameliorating, or slowing the progression of one or more symptomsassociated with the disease or disorder (e.g., schizophrenia or bipolardisorder (in particular, mania)). The full therapeutic effect does notnecessarily occur by administration of one dose, and may occur onlyafter administration of a series of doses. Thus, a therapeuticallyeffective amount may be administered in one or more administrations. Theprecise effective amount needed for a subject will depend upon, forexample, the subject's size, health and age, the nature and extent ofthe cognitive impairment, and the therapeutics or combination oftherapeutics selected for administration, and the mode ofadministration. The skilled worker can readily determine the effectiveamount for a given situation by routine experimentation.

“Subtherapeutic amount” refers to an amount administered of an agent orcompound of the invention that is less than the therapeutic amount, thatis, less than the amount normally used when said agent or compound isadministered alone (i.e., individually and in the absence of othertherapeutic agents or compounds) to treat disorders, such asschizophrenia or bipolar disorder (in particular, mania).

“Analog” is used herein to refer to a compound which functionallyresembles another chemical entity, but does not share the identicalchemical structure. For example, an analog is sufficiently similar to abase or parent compound such that it can substitute for the basecompound in therapeutic applications, despite minor structuraldifferences.

“Derivative” is used herein to refer to the chemical modification of acompound. Chemical modifications of a compound can include, for example,replacement of hydrogen by an alkyl, acyl, or amino group. Many othermodifications are also possible.

The term “prodrug” is art-recognized and is intended to encompasscompounds or agents which, under physiological conditions, are convertedinto a SV2A inhibitor or an antipsychotic. A common method for making aprodrug is to select moieties which are hydrolyzed or metabolized underphysiological conditions to provide the desired compound or agent. Inother embodiments, the prodrug is converted by, for example, anenzymatic activity of the host animal to a SV2A inhibitor or anantipsychotic.

The term “aliphatic” as used herein means a straight chained or branchedalkyl, alkenyl or alkynyl. It is understood that alkenyl or alkynylembodiments need at least two carbon atoms in the aliphatic chain.Aliphatic groups typically contains from 1 (or 2) to 12 carbons, such asfrom 1 (or 2) to 4 carbons.

The term “aryl” as used herein means a monocyclic or bicycliccarbocyclic aromatic ring system. For example, aryl as used herein canbe a C5-C10 monocyclic or C8-C12 bicyclic carbocyclic aromatic ringsystem. Phenyl is an example of a monocyclic aromatic ring system.Bicyclic aromatic ring systems include systems wherein both rings arearomatic, e.g., naphthyl, and systems wherein only one of the two ringsis aromatic, e.g., tetralin.

The term “heterocyclic” as used herein means a monocyclic or bicyclicnon-aromatic ring system having 1 to 3 heteroatom or heteroatom groupsin each ring selected from O, N, NH, S, SO, or SO₂ in a chemicallystable arrangement.

For example, heterocyclic as used herein can be a C5-C10 monocyclic orC8-C12 bicyclic non-aromatic ring system having 1 to 3 heteroatom orheteroatom groups in each ring selected from O, N, NH, S, SO, or SO₂ ina chemically stable arrangement. In a bicyclic non-aromatic ring systemembodiment of “heterocyclyl”, one or both rings may contain saidheteroatom or heteroatom groups. In another bicyclic “heterocyclyl”embodiment, one of the two rings may be aromatic. In yet anotherheterocyclic ring system embodiment, a non-aromatic heterocyclic ringmay optionally be fused to an aromatic carbocycle.

Examples of heterocyclic rings include 3-1H-benzimidazol-2-one,3-(1-alkyl)-benzimidazol-2-one, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino,3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl,3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl,1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl,2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane,benzodithiane, and 1,3-dihydro-imidazol-2-one.

The term “heteroaryl” as used herein means a monocyclic or bicyclicaromatic ring system having 1 to 3 heteroatom or heteroatom groups ineach ring selected from O, N, NH or S in a chemically stablearrangement. For example, heteroaryl as used herein can be a C5-C10monocyclic or C8-C12 bicyclic aromatic ring system having 1 to 3heteroatom or heteroatom groups in each ring selected from O, N, NH or Sin a chemically stable arrangement. In such a bicyclic aromatic ringsystem embodiment of “heteroaryl”:

both rings are aromatic; and

one or both rings may contain said heteroatom or heteroatom groups.

Examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g.,3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g.,5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl,3-thienyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl),pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl,1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl,1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl,pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl,3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, or 4-isoquinolinyl).

The term “cycloalkyl or cycloalkenyl” refers to a monocyclic or fused orbridged bicyclic carbocyclic ring system that is not aromatic. Forexample, cycloalkyl or cycloalkenyl as used herein can be a C5-C10monocyclic or fused or bridged C8-C12 bicyclic carbocyclic ring systemthat is not aromatic. Cycloalkenyl rings have one or more units ofunsaturation. Preferred cycloalkyl or cycloalkenyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,cycloheptyl, cycloheptenyl, norbornyl, adamantyl and decalinyl.

As used herein, the carbon atom designations may have the indicatedinteger and any intervening integer. For example, the number of carbonatoms in a (C1-C4)-alkyl group is 1, 2, 3, or 4. It should be understoodthat these designation refer to the total number of atoms in theappropriate group. For example, in a (C3-C10)-heterocyclyl the totalnumber of carbon atoms and heteroatoms is 3 (as in aziridine), 4, 5, 6(as in morpholine), 7, 8, 9, or 10.

“Pharmaceutically acceptable salt” is used herein to refer to an agentor a compound according to the invention that is a therapeuticallyactive, non-toxic base and acid salt form of the compounds. The acidaddition salt form of a compound that occurs in its free form as a basecan be obtained by treating said free base form with an appropriate acidsuch as an inorganic acid, for example, a hydrohalic such ashydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like;or an organic acid, such as, for example, acetic, hydroxyacetic,propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic,tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic,p-toluenesulfonic, cyclic, salicylic, p-aminosalicylic, pamoic and thelike. See, e.g., WO 01/062726.

Compounds containing acidic protons may be converted into theirtherapeutically active, non-toxic base addition salt form, e. g. metalor amine salts, by treatment with appropriate organic and inorganicbases. Appropriate base salt forms include, for example, ammonium salts,alkali and earth alkaline metal salts, e. g., lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e. g. N-methyl-D-glucamine, hydrabamine salts, and salts withamino acids such as, for example, arginine, lysine and the like.Conversely, said salt forms can be converted into the free forms bytreatment with an appropriate base or acid. Compounds and their saltscan be in the form of a solvate, which is included within the scope ofthe present invention. Such solvates include for example hydrates,alcoholates and the like. See, e.g., WO 01/062726.

As used herein, the term “hydrate” refers to a combination of water witha compound wherein the water retains its molecular state as water and iseither absorbed, adsorbed or contained within a crystal lattice of thesubstrate compound.

As used herein, the term “polymorph” refers to different crystallineforms of the same compound and other solid state molecular formsincluding pseudo-polymorphs, such as hydrates (e.g., bound water presentin the crystalline structure) and solvates (e.g., bound solvents otherthan water) of the same compound. Different crystalline polymorphs havedifferent crystal structures due to a different packing of the moleculesin the lattice. This results in a different crystal symmetry and/or unitcell parameters which directly influences its physical properties suchthe X-ray diffraction characteristics of crystals or powders. Adifferent polymorph, for example, will in general diffract at adifferent set of angles and will give different values for theintensities. Therefore X-ray powder diffraction can be used to identifydifferent polymorphs, or a solid form that comprises more than onepolymorph, in a reproducible and reliable way. Crystalline polymorphicforms are of interest to the pharmaceutical industry and especially tothose involved in the development of suitable dosage forms. If thepolymorphic form is not held constant during clinical or stabilitystudies, the exact dosage form used or studied may not be comparablefrom one lot to another. It is also desirable to have processes forproducing a compound with the selected polymorphic form in high puritywhen the compound is used in clinical studies or commercial productssince Impurities present may produce undesired toxicological effects.Certain polymorphic forms may exhibit enhanced thermodynamic stabilityor may be more readily manufactured in high purity in large quantities,and thus are more suitable for inclusion in pharmaceutical formulations.Certain polymorphs may display other advantageous physical propertiessuch as lack of hygroscopic tendencies, improved solubility, andenhanced rates of dissolution due to different lattice energies.

Many of the compounds useful in the methods and compositions of thisinvention have at least one stereogenic center in their structure. Thisstereogenic center may be present in a R or a S configuration, said Rand S notation is used in correspondence with the rules described inPure Appl. Chem. (1976), 45, 11-30. The invention also relates to allstereoisomeric forms such as enantiomeric and diastereoisomeric forms ofthe compounds or mixtures thereof (including all possible mixtures ofstereoisomers). See, e.g., WO 01/062726.

Furthermore, certain compounds which contain alkenyl groups may exist asZ (zusammen) or E (entgegen) isomers. In each instance, the inventionincludes both mixture and separate individual isomers. Multiplesubstituents on a piperidinyl or the azepanyl ring can also stand ineither cis or trans relationship to each other with respect to the planeof the piperidinyl or the azepanyl ring. Some of the compounds may alsoexist in tautomeric forms. Such forms, although not explicitly indicatedin the formulae described herein, are intended to be included within thescope of the present invention. With respect to the methods andcompositions of the present invention, reference to a compound orcompounds is intended to encompass that compound in each of its possibleisomeric forms and mixtures thereof unless the particular isomeric formis referred to specifically. See, e.g., WO 01/062726.

Description of Methods of the Invention

The methods of this invention comprise administration of a SV2Ainhibitor or a pharmaceutically acceptable salt thereof in combinationwith administration of an antipsychotic or a pharmaceutically acceptablesalt thereof. The agents or compounds of the SV2A inhibitor or theantipsychotic and their pharmaceutically acceptable salts also includehydrates, solvates, polymorphs, and prodrugs of those agents, compounds,and salts.

Methods of Assessing Cognitive Impairment

Animal models serve as an important resource for developing andevaluating treatments for CNS disorders with cognitive impairment.Features that characterize cognitive impairment in animal modelstypically extend to cognitive impairment in humans. Efficacy in suchanimal models is, thus, expected to be predictive of efficacy in humans.The extent of cognitive impairment in an animal model for a CNSdisorder, and the efficacy of a method of treatment for said CNSdisorder may be tested and confirmed with the use of a variety ofcognitive tests.

A Radial Arm Maze (RAM) behavioral task is one example of a cognitivetest, specifically testing spacial memory (Chappell et al.Neuropharmacology 37: 481-487, 1998). The RAM apparatus consists of,e.g., eight equidistantly spaced arms. A maze arm projects from eachfacet of a center platform. A food well is located at the distal end ofeach arm. Food is used as a reward. Blocks can be positioned to prevententry to any arm. Numerous extra maze cues surrounding the apparatus mayalso be provided. After habituation and training phases, spatial memoryof the subjects may be tested in the RAM under control or testcompound-treated conditions. As a part of the test, subjects arepretreated before trials with a vehicle control or one of a range ofdosages of the test compound. At the beginning of each trial, a subsetof the arms of the eight-arm maze is blocked. Subjects are allowed toobtain food on the unblocked arms to which access is permitted duringthis initial “information phase” of the trial. Subjects are then removedfrom the maze for a delay period, e.g., a 60 second delay, a 15 minutedelay, a one-hour delay, a two-hour delay, a six hour delay, a 24 hourdelay, or longer) between the information phase and the subsequent“retention test,” during which the barriers on the maze are removed,thus allowing access to all eight arms. After the delay period, subjectsare placed back onto the center platform (with the barriers to thepreviously blocked arms removed) and allowed to obtain the remainingfood rewards during this retention test phase of the trial. The identityand configuration of the blocked arms vary across trials. The number of“errors” the subjects make during the retention test phase is tracked.An error occurs in the trial if the subjects entered an arm from whichfood had already been retrieved in the pre-delay component of the trial,or if it re-visits an arm in the post-delay session that had alreadybeen visited. A fewer number of errors would indicate better spatialmemory. The number of errors made by the test subject, under varioustest compound treatment regimes, can then be compared for efficacy ofthe test compound in treating CNS disorders with cognitive impairment.

Another cognitive test that may be used to assess the effects of a testcompound on the cognitive impairment of a CNS disorder model animal isthe Morris water maze. A water maze is a pool surrounded with a novelset of patterns relative to the maze. The training protocol for thewater maze may be based on a modified water maze task that has beenshown to be hippocampal-dependent (de Hoz et al., Eur. J. Neurosci.,22:745-54, 2005; Steele and Morris, Hippocampus 9:118-36, 1999). Thesubject is trained to locate a submerged escape platform hiddenunderneath the surface of the pool. During the training trial, a subjectis released in the maze (pool) from random starting positions around theperimeter of the pool. The starting position varies from trial to trial.If the subject does not locate the escape platform within a set time,the experimenter guides and places the subject on the platform to“teach” the location of the platform. After a delay period following thelast training trial, a retention test in the absence of the escapeplatform is given to assess spatial memory. The subject's level ofpreference for the location of the (now absent) escape platform, asmeasured by, e.g., the time spent in that location or the number ofcrossings of that location made by the mouse, indicates better spatialmemory, i.e., treatment of cognitive impairment. The preference for thelocation of the escape platform under different treatment conditions,can then be compared for efficacy of the test compound in treating CNSdisorders with cognitive impairment.

There are various tests known in the art for assessing cognitivefunction in humans, for example and without limitation, the clinicalglobal impression of change scale (CIBIC-plus scale); the Mini MentalState Exam (MMSE); the Neuropsychiatric Inventory (NPI); the ClinicalDementia Rating Scale (CDR); the Cambridge Neuropsychological TestAutomated Battery (CANTAB); the Sandoz Clinical Assessment-Geriatric(SCAG), the Buschke Selective Reminding Test (Buschke and Fuld, 1974);the Verbal Paired Associates subtest; the Logical Memory subtest; theVisual Reproduction subtest of the Wechsler Memory Scale-Revised (WMS-R)(Wechsler, 1997); the Benton Visual Retention Test, or MATRICS consensusneuropsychological test battery which includes tests of working memory,speed of processing, attention, verbal learning, visual learning,reasoning and problem solving and social cognition. See Folstein et al.,J Psychiatric Res 12: 189-98, (1975); Robbins et al., Dementia 5:266-81, (1994); Rey, L'examen clinique en psychologie, (1964); Kluger etal., J Geriatr Psychiatry Neurol 12:168-79, (1999); Marquis et al., 2002and Masur et al., 1994. Also see Buchanan, R. W., Keefe, R. S. E.,Umbricht, D., Green, M. F., Laughren, T., and Marder, S. R. (2011) TheFDA-NIMH-MATRICS guidelines for clinical trial design ofcognitive-enhancing drugs: what do we know 5 years later? Schizophr.Bull. 37, 1209-1217. Another example of a cognitive test in humans isthe explicit 3-alternative forced choice task. In this test, subjectsare presented with color photographs of common objects consisting of amix of three types of image pairs: similar pairs, identical pairs andunrelated foils. The second of the pair of similar objects is referredto as the “lure”. These image pairs are fully randomized and presentedindividually as a series of images. Subjects are instructed to make ajudgment as to whether the objects seen are new, old or similar. A“similar” response to the presentation of a lure stimulus indicatessuccessful memory retrieval by the subject. By contrast, calling thelure stimulus “old” or “new” indicates that correct memory retrieval didnot occur.

Schizophrenia

This invention provides methods and compositions for treatingschizophrenia or bipolar disorder (in particular, mania) using a SV2Ainhibitor or a pharmaceutically acceptable salt thereof in combinationwith an antipsychotic or a pharmaceutically acceptable salt thereof. Incertain embodiments, treatment comprises preventing or slowing theprogression of schizophrenia or bipolar disorder (in particular, mania).Schizophrenia is characterized by a wide spectrum of psychopathology,including positive symptoms such as aberrant or distorted mentalrepresentations (e.g., hallucinations, delusions), negative symptomscharacterized by diminution of motivation and adaptive goal-directedaction (e.g., anhedonia, affective flattening, avolition), and cognitiveimpairment. In certain embodiments, treatment comprises alleviation,amelioration or slowing the progression of one or more positive and/ornegative symptoms, as well as cognitive impairment, associated withschizophrenia. Further, there are a number of other psychiatric diseasessuch as schizotypical and schizoaffective disorder, other acute- andchronic psychoses and bipolar disorder (in particular, mania), whichhave an overlapping symptomatology with schizophrenia. In someembodiments, treatment comprises alleviation, amelioration or slowingthe progression of one or more symptoms, as well as cognitiveimpairment, associated with bipolar disorder (in particular, mania). Themethods and compositions may be used for human patients in clinicalapplications in treating schizophrenia or bipolar disorder (inparticular, mania). The dose of the composition and dosage interval forthe method is, as described herein, one that is safe and efficacious inthose applications.

Cognitive impairments are associated with schizophrenia. They precedethe onset of psychosis and are present in non-affected relatives. Thecognitive impairments associated with schizophrenia constitute a goodpredictor for functional outcome and are a core feature of the disorder.Cognitive features in schizophrenia reflect dysfunction in frontalcortical and hippocampal circuits. Patients with schizophrenia alsopresent hippocampal pathologies such as reductions in hippocampalvolume, reductions in neuronal size and dysfunctional hyperactivity. Animbalance in excitation and inhibition in these brain regions has alsobeen documented in schizophrenic patients suggesting that drugstargeting inhibitory mechanisms could be therapeutic. See, e.g.,Guidotti et al., Psychopharmacology 180: 191-205, 2005; Zierhut, Psych.Res. Neuroimag. 183:187-194, 2010; Wood et al., NeuroImage 52:62-63,2010; Vinkers et al., Expert Opin. Investig. Drugs 19:1217-1233, 2009;Young et al., Pharmacol. Ther. 122:150-202, 2009.

Animal models serve as an important resource for developing andevaluating treatments for schizophrenia. Features that characterizeschizophrenia in animal models typically extend to schizophrenia inhumans. Thus, efficacy in such animal models is expected to bepredictive of efficacy in humans. Various animal models of schizophreniaare known in the art.

One animal model of schizophrenia is protracted treatment withmethionine. Methionine-treated mice exhibit deficient expression ofGAD67 in frontal cortex and hippocampus, similar to those reported inthe brain of postmortem schizophrenia patients. They also exhibitprepulse inhibition of startle and social interaction deficits(Tremonlizzo et al., PNAS, 99: 17095-17100, 2002). Another animal modelof schizophrenia is methylaoxymethanol acetate (MAM)-treatment in rats.Pregnant female rats are administered MAM (20 mg/kg, intraperitoneal) ongestational day 17. MAM-treatment recapitulate a pathodevelopmentalprocess to schizophrenia-like phenotypes in the offspring, includinganatomical changes, behavioral deficits and altered neuronal informationprocessing. More specifically, MAM-treated rats display a decreaseddensity of parvalbumin-positive GABAergic interneurons in portions ofthe prefrontal cortex and hippocampus. In behavioral tests, MAM-treatedrats display reduced latent inhibition. Latent inhibition is abehavioral phenomenon where there is reduced learning about a stimulusto which there has been prior exposure with any consequence. Thistendency to disregard previously benign stimuli, and reduce theformation of association with such stimuli is believed to preventsensory overload. Low latent inhibition is indicative of psychosis.Latent inhibition may be tested in rats in the following manner. Ratsare divided into two groups. One group is pre-exposed to a tone overmultiple trials. The other group has no tone presentation. Both groupsare then exposed to an auditory fear conditioning procedure, in whichthe same tone is presented concurrently with a noxious stimulus, e.g. anelectric shock to the foot. Subsequently, both groups are presented withthe tone, and the rats' change in locomotor activity during tonepresentation is monitored. After the fear conditioning the rats respondto the tone presentation by strongly reducing locomotor activity.However, the group that has been exposed to the tone before theconditioning period displays robust latent inhibition: the suppressionof locomotor activity in response to tone presentation is reduced.MAM-treated rats, by contrast show impaired latent inhibition. That is,exposure to the tone previous to the fear conditioning procedure has nosignificant effect in suppressing the fear conditioning. (see Lodge etal., J. Neurosci., 29:2344-2354, 2009) Such animal models ofschizophrenia may be used to assay the effectiveness of the methods andcompositions of the invention in treating schizophrenia or bipolardisorder (in particular, mania).

MAM-treated rats display a significantly enhanced locomotor response (oraberrant locomotor activity) to low dose D-amphetamine administration.The MAM-treated rats also display a significantly greater number ofspontaneously firing ventral tegmental dopamine (DA) neurons. Theseresults are believed to be a consequence of excessive hippocampalactivity because in MAM-treated rats, the ventral hippocampus (vHipp)inactivation (e.g., by intra-vHipp administration of a sodium channelblocker, tetrodotoxin (TTX), to MAM rats) completely reversed theelevated DA neuron population activity and also normalized the augmentedamphetamine-induced locomotor behavior. The correlation of hippocampaldysfunction and the hyper-responsivity of the DA system is believed tounderlie the augmented response to amphetamine in MAM-treated animalsand psychosis in schizophrenia patients. See Lodge D. J. et al.Neurobiology of Disease (2007), 27(42), 11424-11430. The use ofMAM-treated rats in the above study may be suitable for use to assay theeffectiveness of the methods and compositions of the present inventionin treating schizophrenia or bipolar disorder (in particular, mania).For example, the methods and compositions of this invention maybeevaluated, using MAM-treated animals, for their effects on the centralhippocampus (vHipp) regulation, on the elevated DA neuron populationactivity and on the hyperactive locomotor response to amphetamine in theMAM-treated animals.

In MAM-treated rats, hippocampal (HPC) dysfunction leads to dopaminesystem hyperactivity. A benzodiazepine-positive allosteric modulator(PAM), selective for the α5 subunit of the GABA_(A) receptor,SH-053-2′F—R—CH₃, is tested for its effects on the output of thehippocampal (HPC). The effect of SH-053-2′F—R—CH₃ on the hyperactivelocomotor response to amphetamine in MAM-treated animals is alsoexamined. The α5GABAAR PAM reduces the number of spontaneously active DAneurons in the ventral tegmental area (VTA) of MAM rats to levelsobserved in saline-treated rats (control group), both when administeredsystemically and when directly infused into the ventral HPC. Moreover,HPC neurons in both saline-treated and MAM-treated animals showdiminished cortical-evoked responses following the α5GABAAR PAMtreatment. In addition, the increased locomotor response to amphetamineobserved in MAM-treated rats is reduced following the α5GABA_(A)R PAMtreatment. See Gill K. M et al. Neuropsychopharmacology (2011), 1-9. Theuse of MAM-treated rats in the above study may be suitable for use inthe present invention to assay the effectiveness of the methods andcompositions of the invention in treating schizophrenia or bipolardisorder (in particular, mania). For example, the methods andcompositions of this invention maybe evaluated, using MAM-treatedanimals, for their effects on the output of the hippocampal (HPC) and onthe hyperactive locomotor response to amphetamine in the MAM-treatedanimals.

Administration of MAM to pregnant rats on embryonic day 15 (E15)severely impairs spatial memory or the ability to learn the spatiallocation of four items on an eight-arm radial maze in the offspring. Inaddition, embryonic day 17 (E17) MAM-treated rats are able to reach thelevel of performance of control rats at the initial stages of training,but are unable to process and retrieve spatial information when a 30-mindelay is interposed, indicating a significant impairment in workingmemory. See Gourevitch R. et al. (2004). Behav. Pharmacol, 15, 287-292.Such animal models of schizophrenia may be used to assay theeffectiveness of the methods and compositions of the invention intreating schizophrenia or bipolar disorder (in particular, mania).

Apomorphine-induced climbing (AIC) and stereotype (AIS) in mice isanother animal model useful in this invention. Agents are administeredto mice at a desired dose level (e.g., via intraperitonealadministration). Subsequently, e.g., thirty minutes later, experimentalmice are challenges with apomorphine (e.g., with 1 mg/kg sc). Fiveminutes after the apomorphine injection, the sniffing-licking-gnawingsyndrome (stereotyped behavior) and climbing behavior induced byapomorphine are scored and recorded for each animal. Readings can berepeated every 5 min during a 30-min test session. Scores for eachanimal are totaled over the 30-min test session for each syndrome(stereotyped behavior and climbing). If an effect reached at least of50% inhibition, and ID₅₀ value (95% confidence interval) is calculatedusing a nonlinear least squares calculation with inverse prediction.Mean climbing and stereotype scores can be expressed as a percent ofcontrol values observed in vehible treated (e.g., saline-treated) micethat receive apomorphine. See Grauer S. M. et al. Psychopharmacology(2009) 204, 37-48. This mice model may be used to assay theeffectiveness of the methods and compositions of the invention intreating schizophrenia or bipolar disorder (in particular, mania).

The efficacy of the methods and compositions of this invention intreating schizophrenia may also be assessed in animal models ofschizophrenia or bipolar disorder (in particular, mania), as well ashuman subjects with schizophrenia, using a variety of cognitive testsknown in the art, as discussed above.

SV2A Inhibitors

“Synaptic vesicle protein-2 (SV2)” is a family of synaptic vesicleproteins, which consists of three members, designated SV2A, SV2B, andSV2C. SV2A is the most widely distributed family member, being expressedubiquitously in the brain. The proteins are integral membrane proteinsand have a low-level homology (20-30%) to the twelve transmembranefamily of bacterial and fungal transporter proteins that transportsugar, citrate, and xenobiotics (Bajjalieh et al., Science. 257:1271-1273. (1992)). SV2 family proteins are present in the brain andendocrine cells, and further are present in all synaptic and endocrinevesicles. SV2 proteins are reported to play a role in normal synapticfunction, and functions in a maturation step of primed vesicles thatconverts the vesicles into a Ca(²⁺)- and synaptotagmin-responsive state(Sudhof et al., 2009). Functionally, SV2 proteins are reported toenhance synaptic currents and increase the probability of transmitterrelease by maintaining the size of the readily releasable pool ofvesicles (Custer et al., 2006).

“SV2A inhibitor” refers to any agent, substance or compound that bindsto SV2A and reduces synaptic function by reducing pre-synaptic vesiclerelease (See, e.g., Noyer et al. 1995; Fuks et al. 2003; Lynch et al.2004; Gillard et al. 2006; Custer et al., 2006; Smedt et al., 2007; Yanget al., 2007; Meehan, “Levetiracetam has an activity-dependent effect oninhibitory transmission,” Epilepsia, 2012 Jan. 31; and Example 8 of WO2001/62726, all of which are specifically incorporated herein byreference.) A substance, or a compound or an agent is an SV2A inhibitoreven if it does not itself bind to SV2A, as long as it causes, oraffects the ability of, another compound or agent to bind SV2A or reducesynaptic function by reducing pre-synaptic vesicle release. SV2Ainhibitors, as used herein, include pharmaceutically acceptable salts ofthe inhibitors thereof. They also include hydrates, polymorphs,prodrugs, salts, and solvates of these inhibitors.

Among the SV2A inhibitors or pharmaceutically acceptable salts,hydrates, solvates and polymorphs thereof that are useful in the methodsand compositions of this invention are those disclosed, for example,U.S. patent application Ser. No. 12/580,464, International PatentApplication PCT/US2009/005647, U.S. Patent Application 61/105,847, U.S.Patent Application 61/152,631, and U.S. Patent Application 61/175,536.However, any SV2A inhibitor or a pharmaceutically acceptable salt,hydrate, solvate or polymorph thereof may be used in the methods andcompositions of the invention. In some embodiments, the SV2A inhibitoris selected from the group of SV2A inhibitors referred to inInternational Patent Applications WO2010/144712; WO2010/002869;WO2008/132139; WO2007/065595; WO2006/128693; WO2006/128692;WO2005/054188; WO2004/087658; WO2002/094787; WO2001/062726; U.S. Pat.Nos. 7,465,549; 7,244,747; 5,334,720; 4,696,943; 4,696,942; U.S. PatentApplication Publication Numbers 20090312333; 20090018148; 20080081832;2006258704; and UK Patent Numbers 1,039,113; and 1,309,692 or theirpharmaceutically acceptable salts, hydrates, solvates, or polymorphs.Other SV2A inhibitors may also be used in this invention. Applicantsalso refer to methods of preparing these compounds found in thedocuments cited above. Other synthetic methods may also be used. Thesemethods are well known to those skilled in the art.

In some embodiments of this invention, the SV2A inhibitor is selectedfrom the group consisting of levetiracetam, brivaracetam, andseletracetam or derivatives or analogs or pharmaceutically acceptablesalts, solvates, hydrates, polymorphs, or prodrugs thereof.

In some embodiments of this invention, the SV2A inhibitor islevetiracetam or salts, solvates, hydrates, polymorphs or prodrugsthereof Levetiracetam refers to the International Union of Pure andApplied Chemistry (IUPAC) name of the compound(2S)-2-(2-oxopyrrolidin-1-yl) butanamide). Levetiracetam is a widelyused antiepileptic drug. Levetiracetam binds to a specific site in theCNS: the synaptic vesicle protein 2A (SV2A) (See. e.g., Noyer et al.1995; Fuks et al. 2003; Lynch et al. 2004; Gillard et al. 2006) and hasfurther been shown to directly inhibit synaptic activity andneurotransmission by inhibiting presynaptic neurotransmitter release(Yang et al., 2007).

Among the SV2A inhibitors useful for the methods and compositions ofthis invention are the following:

i) International Patent Application WO 2001/062726:

A compound having the formula I or a pharmaceutically acceptable saltthereof,

wherein X is —CA¹NR⁵R⁶ or —CA¹OR⁷ or —CA¹-R⁸ or CN;

A¹ and A² are independently oxygen, sulfur or —NR⁹;

R¹ is hydrogen, alkyl, aryl or —CH₂—R^(1a) wherein R^(1a) is aryl,heterocycle, halogen, hydroxy, amino, nitro or cyano;

R², R³ and R⁴ are the same or different and each is independentlyhydrogen, halogen, hydroxy, thiol, amino, nitro, nitrooxy, cyano, azido,carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl,ester, ether, aryl, heterocycle, or an oxy derivative, thio derivative,amino derivative, acyl derivative, sulfonyl derivative or sulfinylderivative;

R^(2a), R^(3a) and R^(4a) are the same or different and each isindependently hydrogen, halogen, alkyl, alkenyl, alkynyl or aryl;

R⁵, R⁶, R⁷ and R⁹ are the same or different and each is independentlyhydrogen, hydroxy, alkyl, aryl, heterocycle or an oxy derivative; and

R⁸ is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle or athio derivative;

with the provisos that at least one of as R², R³, R⁴, R^(2a), R^(3a) andR^(4a) is other than hydrogen; and that when the compound is a mixtureof all possible isomers, X is —CONR⁵R⁶, A² is oxygen and R¹ is hydrogen,methyl, ethyl or propyl then substitution on the pyrollidine ring isother than mono-, di-, or tri-methyl or mono-ethyl; and that when R¹,R², R⁴, R^(2a), R^(3a) and R^(4a) are each hydrogen, A² is oxygen and Xis CONR⁵R⁶ then R³ is different from carboxy, ester, amido, substitutedoxo-pyrrolidine, hydroxy, oxy derivative, amino, amino derivatives,methyl, naphthyl, phenyl optionally substituted by oxy derivatives or inthe para position by an halogen atom.

In the definitions set forth below, unless otherwise stated, R¹¹ and R¹²are the same or different and each is independently amido, alkyl,alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl, heterocycle or anoxy derivative, thio derivative, acyl derivative, amino derivative,sulfonyl derivative, or sulfinyl derivative, each optionally substitutedwith any suitable group, including, but not limited to, one or moremoieties selected from lower alkyl or other groups as described below assubstituents for alkyl.

The term “oxy derivative”, as used herein is defined as including —O—R¹¹groups wherein R¹¹ is as defined above except for “oxy derivative”.Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy, acyloxy,oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy,arylsulfinyloxy, aryloxy, aralkoxy or heterocyclooxy such as pentyloxy,allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2-naphthyloxy,2-pyridyloxy, methylenedioxy, carbonate.

The term “thio derivative” as used herein, is defined as including-S—R¹¹groups wherein R¹¹ is as defined above except for “thio derivative”.Non-limiting examples are alkylthio, alkenylthio, alkynylthio andarylthio.

The term “amino derivative” as used herein, is defined asincluding-NHR¹¹ or —NR¹¹R¹² groups wherein R¹¹ and R¹² are as definedabove. Non-limiting examples are mono- or di-alkyl-, alkenyl-, alkynyl-and arylamino or mixed amino.

The term “acyl derivative” as used herein, represents a radical derivedfrom carboxylic acid and thus is defined as including groups of theformula R¹¹—CO—, wherein R¹¹ is as defined above and may also behydrogen. Non-limiting examples are formyl, acetyl, propionyl,isobutyryl, valeryl, lauroyl, heptanedioyl, cyclohexanecarbonyl,crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl, furoyl, nicotinoyl,4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl, oxamoyl.

The term “sulfonyl derivative” as used herein, is defined as including agroup of the formula —SO₂—R¹¹, wherein R¹¹ is as defined above exceptfor “sulfonyl derivative”. Non-limiting examples are alkylsulfonyl,alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.

The term “sulfinyl derivative” as used herein, is defined as including agroup of the formula —SO—R¹¹, wherein R¹¹ is as defined above except for“sulfinyl derivative”. Non-limiting examples are alkylsulfinyl,alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl.

The term “alkyl”, as used herein, is defined as including saturated,monovalent hydrocarbon radicals having straight, branched or cyclicmoieties or combinations thereof and containing 1-20 carbon atoms,preferably 1-6 carbon atoms for non-cyclic alkyl and 3-6 carbon atomsfor cycloalkyl (in these two preferred cases, unless otherwisespecified, “lower alkyl”). Alkyl moieties may optionally be substitutedby 1 to 5 substituents independently selected from the group consistingof halogen, hydroxy, thiol, amino, nitro, cyano, thiocyanato, acyl,acyloxy, sulfonyl derivative, sulfinyl derivative, alkylamino, carboxy,ester, ether, amido, azido, cycloalkyl, sulfonic acid, sulfonamide, thioderivative, oxyester, oxyamido, heterocycle, vinyl, C1-5-alkoxy,C6-10-aryloxy and C6-10-aryl.

Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isoor ter-butyl, and 2,2,2-trimethylethyl each optionally substituted by atleast one substituent selected from the group consisting of halogen,hydroxy, thiol, amino, nitro and cyano, such as trifluoromethyl,trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl.

The term “alkenyl” as used herein, is defined as including both branchedand unbranched, unsaturated hydrocarbon radicals having at least onedouble bond such as ethenyl (=vinyl), 1-methyl-1-ethenyl,2,2-dimethyl-1-ethenyl, 1-propenyl, 2-propenyl (=allyl), 1-butenyl,2-butenyl, 3-butenyl, 4-pentenyl, 1-methyl-4-pentenyl,3-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl, and the like and beingoptionally substituted by at least one substituent selected from thegroup consisting of halogen, hydroxy, thiol, amino, nitro, cyano, aryland heterocycle such as mono- and di-halo vinyl where halo is fluoro,chloro or bromo.

The term “alkynyl” as used herein, is defined as including a monovalentbranched or unbranched hydrocarbon radical containing at least onecarbon-carbon triple bond, for example ethynyl, 2-propynyl (=propargyl),and the like and being optionally substituted by at least onesubstituent selected from the group consisting of halogen, hydroxy,thiol, amino, nitro, cyano, aryl and heterocycle, such as haloethynyl.

When present as bridging groups, alkyl, alkenyl and alkynyl representstraight- or branched chains, C1-12, preferably C1-4-alkylene or C2-12-,preferably C2-4-alkenylene or -alkynylene moieties respectively.

Groups where branched derivatives are conventionally qualified byprefixes such as “n”, “sec”, “iso” and the like (e.g., “n-propyl”,“sec-butyl”) are in the n-form unless otherwise stated.

The term “aryl” as used herein, is defined as including an organicradical derived from an aromatic hydrocarbon consisting of 1-3 rings andcontaining 6-30 carbon atoms by removal of one hydrogen, such as phenyland naphthyl each optionally substituted by 1 to 5 substituentsindependently selected from halogen, hydroxy, thiol, amino, nitro,cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester,ether, amido, azido, sulfonic acid, sulfonamide, alkylsulfonyl,alkylsulfinyl, alkylthio, oxyester, oxyamido, aryl, C1-6-alkoxy,C6-10-aryloxy, C1-6-alkyl, C1-6-haloalkyl. Aryl radicals are preferablymonocyclic containing 6-10 carbon atoms. Preferred aryl groups arephenyl and naphthyl each optionally substituted by 1 to 5 substituentsindependently selected from halogen, nitro, amino, azido, C1-6-alkoxy,C1-6-alkylthio, C1-6-alkyl, C1-6-haloalkyl and phenyl.

The term “halogen”, as used herein, includes an atom of C1, Br, F, I.

The term “hydroxy”, as used herein, represents a group of the formula—OH.

The term “thiol”, as used herein, represents a group of the formula —SH.

The term “cyano”, as used herein, represents a group of the formula —CN.

The term “nitro”, as used herein, represents a group of the formula—NO₂.

The term “nitrooxy”, as used herein, represents a group of the formula—ONO₂.

The term “amino”, as used herein, represents a group of the formula—NH₂.

The term “azido”, as used herein, represents a group of the formula —N₃.

The term “carboxy”, as used herein, represents a group of the formula—COOH.

The term “sulfonic acid”, as used herein, represents a group of theformula —SO₃H.

The term “sulfonamide”, as used herein, represents a group of theformula —SO₂NH₂.

The term “ester”, as used herein is defined as including a group offormula —COO—R¹¹ wherein R¹¹ is as defined above except oxy derivative,thio derivative or amino derivative.

The term “ether” is defined as including a group selected fromC1-50-straight or branched alkyl, or C2-50-straight or branched alkenylor alkynyl groups or a combination of the same, interrupted by one ormore oxygen atoms.

The term “amido” is defined as including a group of formula —CONH₂ or—CONHR¹¹ or CONR¹¹R¹² wherein and R¹² are as defined above.

The term “heterocycle”, as used herein is defined as including anaromatic or non aromatic cyclic alkyl, alkenyl, or alkynyl moiety asdefined above, having at least one O, S and/or N atom interrupting thecarbocyclic ring structure and optionally, one of the carbon of thecarbocyclic ring structure may be replaced by a carbonyl. Non-limitingexamples of aromatic heterocycles are pyridyl, furyl, pyrrolyl, thienyl,isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl,quinolizinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl,indolyl, indolizinyl, purinyl, isoindolyl, carbazolyl, thiazolyl, 1, 2,4-thiadiazolyl, thieno (2,3-b) furanyl, furopyranyl, benzofuranyl,benzoxepinyl, isooxazolyl, oxazolyl, thianthrenyl, benzothiazolyl, orbenzoxazolyl, cinnolinyl, phthalazinyl, quinoxalinyl, phenanthridinyl,acridinyl, perimidinyl, phenanthrolinyl, phenothiazinyl, furazanyl,isochromanyl, indolinyl, xanthenyl, hypoxanthinyl, pteridinyl,5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,pyrrolopyrimidinyl, and pyrazolopyrimidinyl optionally substituted byalkyl or as described above for the alkyl groups. Non-limiting examplesof non aromatic heterocycles are tetrahydrofuranyl, tetrahydropyranyl,piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholino,morpholinyl, 1-oxaspiro (4.5) dec-2-yl, pyrrolidinyl,2-oxo-pyrrolidinyl, sugar moieties (i.e. glucose, pentose, hexose,ribose, fructose, which may also be substituted) or the same which canoptionally be substituted with any suitable group, including but notlimited to one or more moieties selected from lower alkyl, or othergroups as described above for the alkyl groups. The term “heterocycle”also includes bicyclic, tricyclic and tetracyclic, spiro groups in whichany of the above heterocyclic rings is fused to one or two ringsindependently selected from an aryl ring, a cyclohexane ring, acyclohexene ring, a cyclopentane ring, a cyclopentene ring or anothermonocyclic heterocyclic ring or where a monocyclic heterocyclic group isbridged by an alkylene group, such as quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo (2.2.1) heptanyl, 8-azabicyclo(3.2.1)octanyl.

In the above definitions it is to be understood that when a substituentsuch as R², R³, R⁴, R^(2a), R^(3a), R^(4a), R⁵, R⁶, R⁷, R⁸ is attachedto the rest of the molecule via a heteroatom or a carbonyl, a straight-or branched chain, C1-12-, preferably C1-4-alkylene or C2-12, preferablyC2-4-alkenylene or -alkynylene bridge may optionally be interposedbetween the heteroatom or the carbonyl and the point of attachment tothe rest of the molecule.

Preferred examples of X are —COOR⁷ or —CONR⁵R⁶, wherein R⁵, R⁶ and R⁷are preferably hydrogen, C1-4-alkyl, phenyl or alkylphenyl.

Preferably X is carboxy or —CONR⁵R⁶, wherein R⁵ and R⁶ are preferablyhydrogen, C1-4-alkyl, phenyl or alkylphenyl, especially —CONH₂.

Preferably A¹ and A² are each oxygen.

Preferably R¹ is hydrogen, alkyl, especially C1-12 alkyl, particularlylower alkyl or aryl especially phenyl.

Examples of preferred R¹ groups are methyl, ethyl, propyl, isopropyl,butyl, iso- or ter-butyl, 2,2,2-trimethylethyl each optionally attachedvia a methylene bridge or the same substituted by at least one halogenatom such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl,1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

R¹ as ethyl is especially preferred.

Preferably R² and R^(2a) are independently hydrogen, halogen or alkyl,especially lower alkyl.

Examples of preferred R² and R^(2a) groups are independently hydrogen,halogen or methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl,2,2,2-trimethylethyl or the same substituted by at least one halogenatom such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl,1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

Especially at least one and most preferably both of R² and R^(2a) arehydrogen.

Preferably R^(3a), R⁴ and R^(4a) are independently hydrogen, alkyl,especially methyl or ethyl or aryl especially phenyl or aralkyl,especially benzyl.

Examples of preferred R^(3a), R⁴ and R^(4a) groups are independentlyhydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, iso orter-butyl, 2,2,2-trimethylethyl or the same substituted by at least onehalogen atom such as trifluoromethyl, trichloromethyl,2,2,2-trichloroethyl, 1,1-dimethyl-2, 2-dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl.

Especially at least one and most preferably both of R⁴ and R^(4a) arehydrogen.

R^(3a) is particularly hydrogen or alkyl, especially lower alkyl and ismost preferably hydrogen.

Preferably R³ is hydrogen, C1-12-alkyl, especially C1-6-alkyl, eachoptionally substituted by one or more substituents selected fromhydroxy, halogen, cyano, thiocyanato or alkoxy and attached to the ringeither directly or via a thio, sulfinyl, sulfonyl, carbonyl oroxycarbonyl group and optionally, a C1-4-alkylene bridge, particularlymethylene; C2-6-alkenyl or -alkynyl, especially C2-3-alkenyl or -alkynyleach optionally substituted by one or more halogens; azido; cyano;amido; carboxy; triazolyl, tetrazolyl, pyrrolidinyl, pyridyl,1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl,pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or piperazinyleach optionally substituted by one or more substituents selected fromhalogen, C1-6-alkyl and phenyl and attached to the ring either directlyor via a carbonyl group or a C1-4-alkylene bridge, particularlymethylene; naphthyl; or phenyl, phenylalkyl or phenylalkenyl eachoptionally substituted by one or more substituents selected fromhalogen, C1-6-alkyl, C1-6 haloalkyl, C1-6-alkoxy, C1-6-alkylthio, amino,azido, phenyl and nitro and each attached to the ring either directly orvia an oxy, sulfonyl, sulfonyloxy, carbonyl or carbonyloxy group andoptionally additionally a C1-4-alkylene bridge, particularly methylene.

Also, preferably, R³ is C1-6-alkyl optionally substituted by one or moresubstituents selected from halogen, thiocyanato, azido, alkoxy,alkylthio, phenylsulfonyl; nitrooxy; C2-3-alkenyl or -alkynyl eachoptionally substituted by one or more halogens or by acetyl; tetrazolyl,pyridyl, furyl, pyrrolyl, thiazolyl or thienyl; or phenyl or phenylalkyleach optionally substituted by one or more substituents selected fromhalogen, C1-6-alkyl, C1-6 haloalkyl, C1-6-alkoxy, amino, azido, phenyland nitro and each attached to the ring either directly or via asulfonyloxy and optionally additionally a C1-4-alkylene bridge,particularly methylene.

Other examples of preferred R³ groups are hydrogen, halogen or methyl,ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethylor the same substituted by at least one halogen atom such astrifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

R³ is especially C1-4-alkyl optionally substituted by one or moresubstituents selected from halogen, thiocyanato or azido; C2-5-alkenylor -alkynyl, each optionally substituted by one or more halogens;thienyl; or phenyl optionally substituted by one or more substituentsselected from halogen, C1-6-alkyl, C1-6 haloalkyl or azido.

Further examples of preferred R³ groups are C1-6 alkyl and C2-6haloalkenyl.

Preferably R⁵ and R⁶ are independently hydrogen, methyl, ethyl, propyl,isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl, especiallyhydrogen or methyl.

Especially at least one and most preferably both of R⁵ and R⁶ arehydrogen.

Preferably R⁷ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isoor tert-butyl, 2,2,2-trimethylethyl, methoxy, ethoxy, phenyl, benzyl orthe same substituted by at least one halogen atom such astrifluoromethyl, chlorophenyl.

Preferably R⁷ is hydrogen, methyl or ethyl especially hydrogen.

Preferably R⁸ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isoor ter-butyl, 2,2,2-trimethylethyl, phenyl, benzyl or the samesubstituted by at least one halogen atom such as trifluoromethyl,chlorobenzyl.

Preferably R⁸ is hydrogen or methyl.

Combinations of one or more of these preferred compound groups areespecially preferred.

A particular group of compounds of formula I (Compounds 1A) comprisesthose wherein,

A² is oxygen;

X is —CONR⁵R⁶ or —COOR⁷ or —CO—R⁸ or CN;

R¹ is hydrogen or alkyl, aryl, halogen, hydroxy, amino, nitro, cyano;

R², R³, R⁴, are the same or different and each is independently hydrogenor halogen, hydroxy, amino, nitro, cyano, acyl, acyloxy, a sulfonylderivative, a sulfinyl derivative, an amino derivative, carboxy, ester,ether, amido, sulfonic acid, sulfonamide, alkoxycarbonyl, a thioderivative alkyl, alkoxy, oxyester, oxyamido, aryl an oxy derivative,heterocycle, vinyl and R³ may additionally represent C2-5 alkenyl, C2-5alkynyl or azido each optionally substituted by one or more halogen,cyano, thiocyano, azido cyclopropyl, acyl and/or phenyl; orphenylsulfonyloxy whereby any phenyl moiety may be substituted by one ormore halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and/or phenyl;most preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

R^(2a), R^(3a) and R^(4a) are hydrogen;

R⁵, R⁶, R⁷ are the same or different and each is independently hydrogen,hydroxy, alkyl, aryl, heterocycle or oxy derivative; and

R⁸ is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle,alkylthio or thio derivative.

Within these Compounds 1A, R¹ is preferably methyl, ethyl, propyl,isopropyl, butyl, or isobutyl; most preferably methyl, ethyl orn-propyl.

R² and R⁴ are preferably independently hydrogen or halogen or methyl,ethyl, propyl, isopropyl, butyl, isobutyl; and, most preferably, areeach hydrogen.

R³ is preferably C1-5 alkyl, C2-5 alkenyl, C2-C5 alkynyl, cyclopropyl,azido, each optionally substituted by one or more halogen, cyano,thiocyano, azido, alkylthio, cyclopropyl, acyl and/or phenyl; phenyl;phenylsulfonyl; phenylsulfonyloxy, tetrazole, thiazole, thienyl, furyl,pyrrole, pyridine, whereby any phenyl moiety may be substituted by oneor more halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and/or phenyl;most preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

X is preferably —COOH or —COOMe or —COOEt or —CONH₂; most preferably—CONH₂.

A further particular group of compounds of formula I (Compounds 1B)comprises those wherein,

X is —CA¹NH₂, —CA¹NHCH₃ or —CA¹N (CH₃)₂;

R¹ is alkyl or phenyl;

R³ is alkyl, alkenyl, alkynyl, cyano, isothiocyanato, ether, carboxyl,amido, aryl, heterocycle; or

R³ is CH₂R¹⁰ wherein R¹⁰ is hydrogen, cycloalkyl, oxyester,oxyalkylsulfonyl, oxyarylsufonyl, aminoalkylsulfonyl, aminoarylsulfonyl,nitrooxy, cyano, isothiocyanato, azido, alkylthio, arylthio,alkylsulfinyl, alkylsulfonyl, heterocycle, aryloxy, alkoxy ortrifluoroethyl;

R^(3a) is hydrogen, alkyl or aryl (especially with the proviso that whenR^(3a) is hydrogen, R³ other than methyl);

or R³R^(3a) form a cycloalkyl;

and R², R^(2a), R⁴ and R^(4a) are each hydrogen.

Within the compounds of formula I,

R¹ is preferably alkyl especially C1-12-more particularly C1-6-alkyl andis most preferably ethyl;

R², R^(2a), R^(3a) and R^(4a) are preferably hydrogen;

R³ is preferably selected from hydrogen; C1-12-alkyl, especiallyC1-6-alkyl, each optionally substituted by one or more substituentsselected from hydroxy, halogen, cyano, thiocyanato or alkoxy andattached to the ring either directly or via a thio, sulfinyl, sulfonyl,carbonyl or oxycarbonyl group and optionally additionally aC1-4-alkylene bridge, particularly methylene; C2-6-alkenyl or -alkynyl,especially C2-3-alkenyl or -alkynyl, each optionally substituted by oneor more halogens; azido; cyano; amido; carboxy; triazolyl, tetrazolyl,pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl,furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienylor piperazinyl each optionally substituted by one or more substituentsselected from halogen, C1-6-alkyl and phenyl and attached to the ringeither directly or via a carbonyl group or a C1-4-alkylene bridge,particularly methylene; naphthyl; or phenyl, phenylalkyl orphenylalkenyl each optionally substituted by one or more substituentsselected from halogen, C1-6-alkyl, C1-6 haloalkyl, C1-6-alkoxy,C1-6-alkylthio, amino, azido, phenyl and nitro and each attached to thering either directly or via an oxy, sulfonyl, sulfonyloxy, carbonyl orcarbonyloxy group and optionally additionally a C1-4-alkylene bridge,particularly methylene;

R^(3a) is preferably hydrogen or C1-4-alkyl;

R⁴ and R^(4a) are preferably, independently hydrogen, C1-4-alkyl, phenylor benzyl.

A further group of compounds of formula I (Compounds 1C) comprises thosein racemic form wherein, when X is —CONR⁵R⁶ and R¹ is hydrogen, methyl,ethyl or propyl, then substitution on the pyrrolidine ring is other thanmono-, di-, or tri-methyl or mono-ethyl.

A further group of compound of formula I (Compounds 1D) comprises thosein racemic form wherein, when X is —CONR⁵R⁶ and R¹ is hydrogen orC1-6-alkyl, C2-6-alkenyl or -alkynyl or cycloalkyl, each unsubstituted,then substitution in the ring is other than by alkyl, alkenyl oralkynyl, each unsubstituted.

A further particular group of compounds of formula I (Compounds IE)comprises those wherein,

X is —CA¹NH₂;

R¹ is H;

R³ is azidomethyl, iodomethyl, ethyl optionally substituted by 1 to 5halogen atoms, n-propyl optionally substituted by 1 to 5 halogen atoms,vinyl optionally substituted by one or two methyl, and/or 1 to 3 halogenatoms, acetylene optionally substituted by C1-4-alkyl, phenyl orhalogen;

R^(3a) is hydrogen or halogen, preferably fluorine;

and R², R^(2a), R⁴ and R^(4a) are each hydrogen;

as their racemates or in enantiomerically enriched form, preferably thepure enantiomers.

A further particular group of compounds of formula I (Compounds 1F)comprises those wherein,

X is —CA¹NH₂;

R¹ is H;

R³ is C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl optionally substituted byazido, oxynitro, 1 to 6 halogen atoms;

R^(3a) is hydrogen or halogen, preferably fluorine;

and R², R^(2a), R⁴ and R^(4a) are each hydrogen; as their racemates orin enantiomerically enriched form, preferably the pure enantiomers.

In all the above mentioned scopes when the carbon atom to which R¹ isattached is asymmetric it is preferably in the “S”-configuration.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:

-   (2S)-2-[4-(bromomethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidinyl]butanamide;-   (2S)-2-(2-oxo-4-phenyl-1-pyrrplidinyl)butanamide;-   (2S)-2-[4-(iodomethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(chloromethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   {1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl}methyl    4-methylbenzenesulfonate;-   (2S)-2-[(4R)-4-(azidomethyl)-2-oxopyrrolidinyl]butanamide;-   2-[4-(2, 2-dibromovinyl)-2-oxo-1-pyrrolidinyl]butanamide;-   {1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl}methyl    nitrate;-   (2S)-2-[2-oxo-4-(1H-tetraazol-1-ylmethyl)-1-pyrrolidinyl]butanamide;-   2-(2-oxo-4-vinyl-1-pyrrolidinyl)butanamide;-   2-{2-oxo-4-[(phenylsulfonyl) methyl]-1-pyrrolidinyl]butanamide;-   (2S)-2-[(4R)-4-(2, 2-dibromovinyl)-2-oxopyrrolidinyl]butanamide;-   (2S)-2-[(4S)-4-(2, 2-dibromovinyl)-2-oxopyrrolidinyl]butanamide;-   (2S)-2-[4-(isothiocyanatomethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[2-oxo-4-(1,3-thiazol-2-yl)-1-pyrrolidinyl]butanamide;-   (2S)-2-[2-oxo-4-(2-thienyl)-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(2-methoxyphenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(3-methoxyphenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(4-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[2-oxo-4-(3-thienyl)-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(3-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[2-oxo-4-(3-thienyl)-1-pyrrolidinyl]butanamide;-   (2S)-2-[(4S)-2-oxo-4-vinylpyrrolidinyl]butanamide;-   (2S)-2-[(4R)-2-oxo-4-vinylpyrrolidinyl]butanamide;-   2-[4-(2-bromophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[2-oxo-4-(3-pyridinyl)-1-pyrrolidinyl]butanamide;-   (2S)-2-(4-[1, 1′-biphenyl]-4-yl-2-oxo-1-pyrrolidinyl)butanamide;-   (2S)-2-{4-[(methylsulfanyl) methyl]-2-oxo-1-pyrrolidinyl}butanamide;-   2-[4-(iodomethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[(4R)-4-(iodomethyl)-2-oxo-1-pyrrolidinyl]pentanamide;-   (2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidinyl]propanamide;-   2-(2-oxo-4-propyl-1-pyrrolidinyl)propanamide;-   2-(2-oxo-4-propyl-1-pyrrolidinyl)butanamide;-   2-(2-oxo-4-pentyl-1-pyrrolidinyl)butanamide;-   (2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidinyl]-N-methylbutanamide;-   (2S)-2-(4-neopentyl-2-oxo-1-pyrrolidinyl)butanamide;-   (2S)-2-(4-ethyl-2-oxo-1-pyrrolidinyl)butanamide;-   2-[4-(2,2-difluorovinyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[4-(2,2-difluoroethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[(4S)-2-oxo-4-propylpyrrolidinyl]butanamide;-   (2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butanamide;-   2-{4-[(Z)-2-fluoroethenyl]-2-oxo-1-pyrrolidinyl}butanamide;-   2-[4-(2-methyl-1-propenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-(4-butyl-2-oxo-1-pyrrolidinyl)butanamide;-   2-[4-(cyclopropylmethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-(4-isobutyl-2-oxo-1-pyrrolidinyl)butanamide;-   2-[4-(4-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[4-(3-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-{2-oxo-4-[2-(trifluoromethyl)phenyl]-1-pyrrolidinyl}butanamide;-   2-[4-(2-fluorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[4-(3-methylphenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[2-oxo-4-(2-phenyl ethyl)-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(3-bromophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-{4-[3,5-bis(trifluoromethyl)phenyl]-2-oxo-1-pyrrolidinyl}butanamide;-   2-[4-(3,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[4-(2,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[4-(2-furyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[2-oxo-4-(3-phenylpropyl)-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(3,5-dibromophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[4-(3,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-(2-oxo-4-propyl-1-pyrrolidinyl)butanamide;-   2-[4-(3-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-(4-ethynyl-2-oxo-1-pyrrolidinyl) butanamide;-   2-[4-(2-fluorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(cyclopropylmethyl)-2-oxo-1-pyrrolidinyl}butanamide;-   (2S)-2-[(4S)-4-(2, 2-difluorovinyl)-2-oxopyrrolidinyl]butanamide;-   (2S)-2-[2-oxo-4-(3, 3, 3-trifluoropropyl)-1-pyrrolidinyl]butanamide;-   2-[4-(3-methylphenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(cyclopropylmethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[(4R)-4-(2, 2-difluorovinyl)-2-oxopyrrolidinyl]butanamide;-   (2S)-2-[2-oxo-4-(1H-pyrrol-1-yl)-1-pyrrolidinyl]butanamide;-   (2S)-2-(4-allyl-2-oxo-1-pyrrolidinyl)butanamide;-   (2S)-2-[4-(2-iodopropyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-(4-allyl-2-oxo-1-pyrrolidinyl)butanamide;-   (2S)-2-[2-oxo-4-(2-oxopropyl)-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(2-bromo-1H-pyrrol-1-yl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-(4-methyl-2-oxo-4-propyl-1-pyrrolidinyl)butanamide;-   (2R)-2-[4-(2, 2-dichlorovinyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[4-(bromoethynyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[(4S)-4-(2, 2-difluoropropyl)-2-oxopyrrolidinyl]butanamide;-   (2S)-2-[4-(bromoethynyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-(2-oxo-4-propyl-1-pyrrolidinyl)pentanamide;-   3-cyclopropyl-2-(2-oxo-4-propyl-1-pyrrolidinyl)propanamide;-   2-(2-oxo-4-propyl-1-pyrrolidinyl)-3-(1,3-thiazol-4-yl)propanamide;-   2-(2-oxo-4-propyl-1-pyrrolidinyl)-4-pentenamide;-   (2S)-2-[(4R)-2-oxo-4-vinylpyrrolidinyl]butanamide;

including all isomeric forms and mixtures thereof or a pharmaceuticallyacceptable salt thereof.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:

-   (2S)-2-[(4S)-4-(2, 2-difluorovinyl)-2-oxopyrrolidinyl]butanamide;-   (2S)-2-[(4S)-2-oxo-4-propylpyrrolidinyl]butanamide;-   (2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butanamide.

ii) International Patent Application WO 2002/094787:

Compounds of the Formula I

wherein n represents 0 or 1 whereby R¹ is not existent when n=0 and R¹is existent when n=1;

A¹ represents an oxygen or a sulfur atom;

X is —CONR⁷R⁸, —COOR⁹, —CO—R¹⁰ or CN;

R¹ when existent, R², R³, R⁴ and R⁵ are the same or different and eachis independently hydrogen, halogen, hydroxy, thiol, amino, nitro,nitrooxy, cyano, azido, carboxy, amido, sulfonic acid, sulfonamide,alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle, or an oxyderivative, thio derivative, amino derivative, acyl derivative, sulfonylderivative or sulfinyl derivative,

provided that at least one of the substituents R chosen from R¹ whenexistent, R², R³, R⁴ or R⁵ is not hydrogen;

R⁶ is hydrogen, alkyl, aryl or —CH₂—R^(6a) wherein R^(6a) is aryl,heterocycle, halogen, hydroxy, amino, nitro or cyano;

R⁷, R⁸ and R⁹ are the same or different and each is independentlyhydrogen, hydroxy, alkyl, aryl, heterocycle or an oxy derivative; and

R¹⁰ is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle or athio derivative;

their pharmaceutically acceptable salts, geometrical isomers (includingcis and trans, Z and E isomers), enantiomers, diastereoisomers andmixtures thereof (including all possible mixtures of stereoisomers).

In the above formula, at least one substituent R¹ to R⁵ is differentfrom hydrogen. Some non-substituted compounds are referred to in U.S.Pat. Nos. 5,468,733 and 5,516,759. U.S. Pat. No. 5,468,733 refers tonon-ring substituted 2-oxo-1-pyrrolidinyl and 2-oxo-1-piperidinylderivatives as inhibitors of the oncogene Ras protein. In particular,these compounds block the ability of Ras to transform normal cells tocancer cells, and therefore can be included in several chemotherapeuticcompositions for treating cancer.

U.S. Pat. No. 5,516,759 refers to non-ring substituted2-oxo-1-pyrrolidinyl, 2-oxo-1-piperidinyl and azepanyl derivativespresent at the N-terminus of dodecapeptides possessing LHRH (luteinizinghormone-releasing hormone) antagonistic activity. Such LHRH antagonistsare useful in the treatment of a variety of conditions in whichsuppression of sex steroids plays a key role including contraception,delay of puberty, treatment of benign prostatic hyperplasia a. o.

In the definitions set forth below, unless otherwise stated, R¹¹ and R¹²are the same or different and each is independently amido, alkyl,alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl. heterocycle or anoxy derivative, thio derivative, acyl derivative, amino derivative,sulfonyl derivative, or sulfinyl derivative, each optionally substitutedwith any suitable group, including, but not limited to, one or moremoieties selected from lower alkyl or other groups as described below assubstituents for alkyl.

The term “oxy derivative”, as used herein, is defined as including-O—R¹¹groups wherein R¹¹ is as defined above except for “oxy derivative”.Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy, acyloxy,oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy,arylsulfinyloxy, aryloxy, aralkoxy or heterocyclooxy such as pentyloxy,allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2-naphthyloxy,2-pyridyloxy, methylenedioxy, carbonate.

The term “thio derivative”, as used herein, is defined asincluding-S—R¹¹ groups wherein R¹¹ is as defined above except for “thioderivative”. Non-limiting examples are alkylthio, alkenylthio,alkynylthio and arylthio.

The term “amino derivative”, as used herein, is defined as including—NHR¹¹ or —NR¹¹R¹² groups wherein R¹¹ and R¹² are as defined above.Non-limiting examples are mono- or di-alkyl-, alkenyl-, alkynyl- andarylamino or mixed amino.

The term “acyl derivative”, as used herein, represents a radical derivedfrom carboxylic acid and thus is defined as including groups of theformula R¹¹—CO—, wherein R¹¹ is as defined above and may also behydrogen. Preferred are acyl derivatives of formula —COR¹¹ wherein R¹¹is selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkenyl,heterocyle and aryl. Non-limiting examples are formyl, acetyl,propionyl, isobutyryl, valeryl, lauroyl, heptanedioyl,cyclohexanecarbonyl, crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl,furoyl, nicotinoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl,oxamoyl.

The term “sulfonyl derivative”, as used herein, is defined as includinga group of the formula —SO₂—R¹¹, wherein R¹¹ is as defined above exceptfor “sulfonyl derivative”. Non-limiting examples are alkylsulfonyl,alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.

The term “sulfinyl derivative”, as used herein, is defined as includinga group of the formula —SO—R¹¹, wherein R¹¹ is as defined above exceptfor “sulfinyl derivative”. Non-limiting examples are alkylsulfinyl,alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl.

The term “alkyl”, as used herein, is defined as including saturated,monovalent hydrocarbon radicals having straight, branched or cyclicmoieties or combinations thereof and generally containing 1-20 carbonatoms, most often 1 to 12 carbon atoms, preferably 1-7 carbon atoms fornon-cyclic alkyl and 3-7 carbon atoms for cycloalkyl (in these twopreferred cases, unless otherwise specified, “lower alkyl”), eachoptionally substituted by, preferably 1 to 5, substituents independentlyselected from the group consisting of halogen, hydroxy, thiol, amino,nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulfinylderivative, alkylamino, carboxy, ester, ether, amido, azido, cycloalkyl,sulfonic acid, sulfonamide, thio derivative, alkylthio, oxyester,oxyamido, heterocycle, vinyl, alkoxy (preferably C1-5), aryloxy(preferably C6-10) and aryl (preferably C6-10).

Preferred are alkyl groups containing 1 to 7 carbon atoms, eachoptionally substituted by one or more substituents selected fromhydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio,cyclopropyl, acyl and phenyl. Most preferred are C1-4 alkyl and C3-7cycloalkyl, each optionally substituted by one or more hydroxy, halogen,lower alkyl or/and azido.

Most preferred alkyl groups are hydroxymethyl, propyl, butyl, 2,2,2-trifluoroethyl, 2-bromo-2,2-difluoroethyl,2-chloro-2,2-difluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl,iodomethyl, azidomethyl, 2,2-difluoropropyl, 2-iodo-2,2-difluoroethyl.

The term “lower alkyl”, as used herein, and unless otherwise specified,refers to C₁ to C₇ saturated straight, branched or cyclic hydrocarbon.Non limiting examples are methyl, ethyl, propyl, isopropyl, butyl,tertiobutyl, pentyl, cyclopropyl, cyclopentyl, isopentyl, neopentyl,hexyl, isohexyl, cyclohexyl, 3-methypentyl, 2,2-dimethylbutyl,optionally substituted with any suitable group, including but notlimited to one or more moieties selected from groups as described abovefor the alkyl groups. Preferably, lower alkyl is methyl.

The term “alkenyl”, as used herein, is defined as including bothbranched and unbranched, unsaturated hydrocarbon radicals having atleast one double bond, and being optionally substituted by at least onesubstituent selected from the group consisting of halogen, hydroxy,thiol, amino, thiocyanato, azido, alkylthio, cycloalkyl, acyl, nitro,cyano, aryl and heterocycle.

Preferred alkenyl groups are C2-C12 alkenyls, especially C2-6 alkenyls,such as ethenyl (=vinyl), 1-methyl-1-ethenyl, 2,2-dimethyl-1-ethenyl,1-propenyl, 2-propenyl (=allyl), 1-butenyl, 2-butenyl, 3-butenyl,4-pentenyl, 1-methyl-4-pentenyl, 3-methyl-1-pentenyl, 1-hexenyl,2-hexenyl and the like, optionally being substituted by one or moresubstituents selected from halogen, cyano, thiocyanato, azido,alkylthio, cycloalkyl, phenyl and acyl. Most preferred is vinyl,optionally substituted by one or more halogen or/and lower alkyl, andespecially 2,2-difluorovinyl, 2,2-dibromovinyl and 2,2-dichlorovinyl.

The term “alkynyl” as used herein, is defined as including a monovalentbranched or unbranched hydrocarbon radical containing at least onecarbon-carbon triple bond, for example ethynyl, 2-propynyl (=propargyl),and the like, and being optionally substituted by at least onesubstituent selected from the group consisting of halogen, hydroxy,thiol, amino, nitro, cyano, aryl, heterocycle, thiocyanato, azido,alkylthio, alkyl and acyl.

Preferred alkynyl groups are C2-12 alkynyl, especially C2-6 alkynyl,optionally being substituted by one or more substituents selected fromhalogen, cyano, thiocyanato, azido, alkylthio, acyl, aryl such as phenyland alkyl, preferably cycloalkyl.

Most preferred are ethynyl, propynyl and butynyl, optionally substitutedby lower alkyl or/and halogen, and especially 1-propynyl,cyclopropylethynyl, 3-methyl-1-butynyl and 3,3,3-trifluoro-1-propynyl.

When present as bridging groups, alkyl, alkenyl and alkynyl representstraight- or branched chains, C1-12, preferably C1-4-alkylene or C2-12-,preferably C2-4-alkenylene or -alkynylene moieties respectively.

Groups where branched derivatives are conventionally qualified byprefixes such as “n”, “sec”, “iso” and the like (e. g. “n-propyl”,“sec-butyl”) are in the n-form unless otherwise stated.

The term “aryl”, as used herein, is defined as including an organicradical derived from an aromatic hydrocarbon consisting of at least onering, most often 1 to 3 rings and generally containing 6-30 carbon atomsby removal of one hydrogen, such as phenyl and naphthyl, each optionallysubstituted by one or more substituents independently selected fromhalogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl,sulfinyl, alkylamino, carboxy, ester, ether, amido, azido, sulfonicacid, sulfonamide, alkylsulfonyl, alkylsulfinyl, C1-6-alkylthio,oxyester, oxyamido, aryl, C1-6-alkoxy, C6-10-aryloxy, C1-6-alkyl,C1-6-haloalkyl. Aryl radicals are preferably monocyclic or bicycliccontaining 6-10 carbon atoms. Preferred aryl groups are phenyl andnaphthyl each optionally substituted by one or more substituentsindependently selected from halogen, nitro, amino, azido, C1-6-alkoxy,C1-6-alkyl, C1-6-haloalkyl, sulfonyl and phenyl.

Preferred aryl is phenyl, optionally substituted by one or more halogen,lower alkyl, azido or nitro, such as 3-chlorophenyl and 3-azidophenyl.

The term “halogen”, as used herein, includes an atom of C1, Br, F, I.

The term “hydroxy”, as used herein, represents a group of the formula—OH.

The term “thiol”, as used herein, represents a group of the formula —SH.

The term “cyano”, as used herein, represents a group of the formula —CN.

The term “nitro”, as used herein, represents a group of the formula—NO₂.

The term “nitrooxy”, as used herein, represents a group of the formula—ONO₂.

The term “amino”, as used herein, represents a group of the formula—NH₂.

The term “azido”, as used herein, represents a group of the formula —N₃.

The term “carboxy”, as used herein, represents a group of the formula—COOH.

The term “sulfonic acid”, as used herein, represents a group of theformula —SO₃H.

The term “sulfonamide”, as used herein, represents a group of theformula —SO₂NH₂.

The term “ester”, as used herein, is defined as including a group offormula —COO—R¹¹ wherein R¹¹ is as defined above except oxy derivative,thio derivative or amino derivative. Preferred are esters of formula—COOR¹¹ wherein R¹¹ is selected from C1-12 alkyl, C2-12 alkenyl, C2-12alkynyl and aryl. Most preferred are esters where R¹¹ is a lower alkyl,especially methyl.

The term “ether” is defined as including a group selected fromC1-50-straight or branched alkyl, or C2-50-straight or branched alkenylor alkynyl groups or a combination of the same, interrupted by one ormore oxygen atoms.

The term “amido” is defined as including a group of formula —CONH₂ or—CONHR¹¹ or —CONR¹¹R¹² wherein R¹¹ and R¹² are as defined above.

The term “heterocycle”, as used herein, is defined as including anaromatic or non aromatic cyclic alkyl, alkenyl, or alkynyl moiety asdefined above, having at least one O, S and/or N atom interrupting thecarbocyclic ring structure and optionally, one of the carbon of thecarbocyclic ring structure may be replaced by a carbonyl, and optionallybeing substituted with any suitable group, including but not limited toone or more moieties selected from lower alkyl, or other groups asdescribed above for the alkyl groups. Non-limiting examples ofheterocycles are pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl,triazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl,quinolizinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl,indolyl, indolizinyl, purinyl, isoindolyl, carbazolyl, thiazolyl,1,2,4-thiadiazolyl, thiomorpholinyl, thieno (2,3-b) furanyl,furopyranyl, benzofuranyl, benzoxepinyl, isooxazolyl, oxazolyl,thianthrenyl, benzothiazolyl, or benzoxazolyl, cinnolinyl, phthalazinyl,quinoxalinyl, 1-oxidopyridyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenothiazinyl, furazanyl, benzodioxolyl, isochromanyl,indolinyl, xanthenyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl,5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,pyrrolopyrimidinyl, pyrazolopyrimidinyl, tetrahydrofuranyl,tetrahydropyranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl,morpholino, morpholinyl, 1-oxaspiro (4.5) dec-2-yl, pyrrolidinyl,2-oxo-pyrrolidinyl, sugar moieties (i. e. glucose, pentose, hexose,ribose, fructose, which may also be substituted) optionally substitutedby alkyl or as described above for the alkyl groups. The term“heterocycle” also includes bicyclic, tricyclic and tetracyclic, spirogroups in which any of the above heterocyclic rings is fused to one ortwo rings independently selected from an aryl ring, a cyclohexane ring,a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or anothermonocyclic heterocyclic ring or where a monocyclic heterocyclic group isbridged by an alkylene group, such as quinuclidinyl, 7-azabicyclo(2.2.1) heptanyl, 7-oxabicyclo (2.2.1) heptanyl, 8-azabicyclo (3.2.1)octanyl.

The heterocycle is preferably selected from triazolyl, tetrazolyl,pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl,furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyland piperazinyl, each optionally substituted by one or more substituentsselected from halogen, alkyl, substituted alkyl, alkoxy, nitro, amino,acyl and phenyl.

More preferably the heterocycle is selected from tetrazolyl,pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl and thienyl, eachoptionally substituted by one or more substituents selected fromhalogen, alkyl, halogen substituted alkyl, acyl, alkoxy, nitro, aminoand phenyl, and especially from 2- and 3-thienyl, optionally substitutedby one or more halogen, acyl such as formyl, cyano and/or lower alkyl,such as methyl.

In the above definitions it is to be understood that when a substituentsuch as R¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, R¹⁰ is attached to the rest ofthe molecule via a heteroatom or a carbonyl, a straight- or branchedchain, C1-12-, preferably C1-4-alkylene or C2-12, preferablyC2-4-alkenylene or -alkynylene bridge may optionally be interposedbetween the heteroatom or the carbonyl and the point of attachment tothe rest of the molecule.

The term “R substituent” refers to R¹, R², R³, R⁴ or R⁵, independently.According to a preferred embodiment, a compound of formula I is asdefined above wherein n represents 0. The compound is a 6-ring structure(2-thioxo- or 2-oxo-piperidinyl derivative) wherein R¹ is not existentsince n=0, and is depicted by the formula (I-A).

According to a following embodiment, the compound of formula I is asdefined above wherein n represents 1. The compound is a 7-ring structure(2-thioxo- or 2-oxo-azepanyl derivative) wherein R¹ is existent sincen=1 and depicted by the formula (I-B).

According to a more preferred embodiment, said compound is as definedabove wherein n=0, R³ and/or R⁴ are different from hydrogen and R² andR⁵ represent hydrogen.

According to another more preferred embodiment, said compound is asdefined above wherein n=1, R², R³ and/or R⁴ are different from hydrogenand wherein R¹ and R⁵ represent hydrogen.

According to a yet more preferred embodiment, said compound is asdefined above wherein only one R substituent chosen from R³ or R⁴ whenn=0 or from R², R³ or R⁴ when n=1, is different from hydrogen and theremaining R substituent(s) is/are hydrogen. We hereby refer to amono-substituted 2-thioxo- or 2-oxo-piperidinyl or 2-thioxo- or2-oxo-azepanyl derivatives.

According to another preferred embodiment, compounds of formula I are asdefined above wherein A¹ represents an oxygen atom. We hereby refer to2-oxo-piperidinyl or 2-oxo-azepanyl derivatives.

According to another preferred embodiment, compounds of formula I are asdefined above wherein X is CONR⁷R⁸, especially CONH₂. We hereby refer toamido derivatives of 2-oxo (or thioxo)-piperidinyl or 2-oxo (orthioxo)-azepanyl.

According to another preferred embodiment, compounds of formula I are asdefined above wherein R⁶ represents hydrogen, C1-4 alkyl, or aCH₂—R^(6a) group wherein R^(6a) represents a heterocycle. Mostpreferably R⁶ is a C1-4 alkyl, especially ethyl. When R⁶ is ethyl werefer to 2-(2-oxo (or thioxo)-1-piperidinyl) butanamide or 2-(2-oxo (orthioxo)-1-azepanyl) butanamide derivatives.

According to another preferred embodiment, compounds of formula I are asdefined above wherein the carbon atom to which R⁶ is attached is of theS configuration. In case where R⁶ is ethyl, A is oxygen and X is CONR⁷R⁸we refer then to (2S)-2-(2-oxo-1-piperidinyl) butanamide or(2S)-2-(2-oxo-1-azepanyl) butanamide derivatives.

According to a preferred embodiment, the compound is as defined abovewherein R² when n=1, R³ and R⁴ are the same or different and each isindependently hydrogen, halogen, nitro, nitrooxy, cyano, carboxy, amido,sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl,heterocycle, acyl derivative, sulfonyl derivative or sulfinylderivative;

R¹ when existent, R² when n=0 and R⁵ are hydrogen;

R⁶ is hydrogen, alkyl, aryl or —CH₂—R^(6a) wherein R^(6a) is aryl,heterocycle, halogen, hydroxy, amino, nitro or cyano;

According to this preferred embodiment, the compound is generally suchthat when R⁶ is benzyl, X is —COOCH₃ and n=1, R² is different frommethyl when R³ and R⁴ are both hydrogen and R⁴ is different from methylwhen R² and R³ are both hydrogen.

According to another preferred embodiment, the compound is as definedabove wherein R² when n=1, R³ and R⁴ are the same or different and eachis independently hydrogen; cyano; carboxy; amido;

C1-12 alkyl, each optionally substituted by one or more substituentsselected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido,alkyltio, cycloalkyl, acyl, aryl and heterocycle;

C2-12 alkenyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryland acyl;

C2-12 alkynyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryland acyl; acyl derivative of formula —CO—R¹¹, wherein R¹¹ is selectedfrom C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, heterocycle and aryl;

ester of formula —CO—O—R¹¹ wherein R¹¹ is selected from C1-12 alkyl,C2-12 alkenyl, C2-12 alkynyl and aryl;

heterocycle selected from triazolyl, tetrazolyl, pyrrolidinyl, pyridyl,1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl,pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl and piperazinyl,each optionally substituted by one or more substituents selected fromhalogen, alkyl, substituted alkyl, alkoxy, nitro, amino, acyl andphenyl;

aryl, each optionally substituted by one or more substituents selectedfrom C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, amino,azido, sulfonyl, aryl and nitro.

According to another preferred embodiment, the compound is as definedabove, wherein R² when n=1, R³ and R⁴ are the same or different and eachis independently hydrogen;

C1-7 alkyl, each optionally substituted by one or more substituentsselected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido,alkyltio, cyclopropyl, acyl and phenyl;

C2-6 alkenyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl,phenyl and acyl;

C2-6 alkynyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl,phenyl and acyl;

heterocycle selected from tetrazolyl, pyrrolidinyl, pyridyl, furyl,pyrrolyl, thiazolyl and thienyl, each optionally substituted by one ormore substituents selected from halogen, alkyl, halogen substitutedalkyl, acyl, alkoxy, nitro, amino and phenyl;

phenyl, each optionally substituted by one or more substituents selectedfrom C1-6 alkyl, halogen substituted alkyl, halogen, alkoxy, amino,azido, sulfonyl, phenyl and nitro.

According to another preferred embodiment, the compound is as definedabove wherein at least one of the R substituents chosen from the groupR², R³ and R⁴ when n=1 or from the group R³ and R⁴ when n=0, representsindependently C1-4-alkyl or C3-7-cycloalkyl, optionally substituted byone or more halogen, hydroxy, lower alkyl and/or azido.

According to another preferred embodiment, the compound is as definedabove wherein at least one of the R substituents chosen from the groupR², R³ and R⁴ when n=1 or from the group R³ and R⁴ when n=0, representsindependently vinyl, optionally substituted by one or more halogenor/and lower alkyl.

According to another preferred embodiment, the compound is as definedabove wherein at least one of the R substituents chosen from the groupR², R³ and R⁴ when n=1 or from the group R³ and R⁴ when n=0, representsindependently ethynyl, propynyl or butynyl, optionally substituted byone or more halogen and/or lower alkyl.

According to another preferred embodiment, the compound is as definedabove wherein at least one of the R substituents chosen from the groupR², R³ and R⁴ when n=1 or from the group R³ and R⁴ when n=0, representsindependently phenyl, optionally substituted by one or more halogen,lower alkyl, azido and/or nitro.

According to another preferred embodiment, the compound is as definedabove wherein at least one of the R substituents chosen from the groupR², R³ and R⁴ when n=1 or from the group R³ and R⁴ when n=0, representsindependently 2- or 3-thienyl, optionally substituted by one or morehalogen, acyl, cyano or/and lower alkyl.

According to a particular preferred embodiment, the compound is asdefined above wherein at least one of the R substituents chosen from thegroup R³, R⁴ and R² when n=1 or from the group R³ and R⁴ when n=0, ishydroxymethyl, propyl, butyl, 3,3,3-trifluoropropyl,2,2,2-trifluoroethyl, cyclopropylmethyl, iodomethyl, azidomethyl,2-thienyl, 3-thienyl, phenyl, 3-chlorophenyl, 3-azidophenyl,2,2-difluorovinyl, 2,2-dibromovinyl, 2, 2-dichlorovinyl, 2-ethynyl,5-methyl-2-thienyl, 5-formyl-2-ethynyl, 5-cyano-2-thienyl,3-bromo-2-thienyl, 4-methyl-2-thienyl, 3,3,3-trifluoro-1-propynyl,1-propynyl, cyclopropylethynyl, 3-methyl-1-butynyl, 1-butynyl,2,2-difluoropropyl, 2-chloro-2,2-difluoroethyl,2-bromo-2,2-difluoroethyl and 2-iodo-2,2-difluoroethyl.

According to yet another preferred embodiment, the compound is asdefined above wherein R¹, R², R⁴ and R⁵ are hydrogen.

According to even another preferred embodiment, the compound is asdefined above wherein R¹, R², R³ and R⁵ are hydrogen.

According to even another preferred embodiment, the compound is asdefined above wherein n=1 and R′, R³, R⁴ and R⁵ are hydrogen.

In all the above-mentioned scopes when the carbon atom to which R⁶ isattached is asymmetric it is preferably in the “S”-configuration.

Representative compounds useful in the methods and compositions of thisinvention as defined above are selected from the group consisting of

-   2-[5-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,-   2-(2-oxo-5-propyl-1-piperidinyl)butanamide,-   2-[2-oxo-5-(3,3,3-trifluoropropyl)-1-piperidinyl]butanamide,-   2-[5-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-(2-oxo-5-phenyl-1-piperidinyl)butanamide,-   2-[2-oxo-5-(2-thienyl)-1-piperidinyl]butanamide,-   2-[2-oxo-5-(3-thienyl)-1-piperidinyl]butanamide,-   2-[5-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(2, 2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(2, 2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(2, 2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide,-   2-(5-ethynyl-2-oxo-1-piperidinyl)butanamide,-   2-[5-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[2-oxo-5-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl]butanamide,-   2-[2-oxo-5-(1-propynyl)-1-piperidinyl]butanamide,-   2-[5-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(1-butynyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(2,2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,-   2-(2-oxo-4-propyl-1-piperidinyl)butanamide,-   2-[2-oxo-4-(3,3,3trifluoropropyl)-1-piperidinyl]butanamide,-   2-[4-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-(2-oxo-4-phenyl-1-piperidinyl)butanamide,-   2-[2-oxo-4-(2-thienyl)-1-piperidinyl]butanamide,-   2-[2-oxo-4-(3-thienyl)-1-piperidinyl]butanamide,-   2-[4-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide,-   2-(4-ethynyl-2-oxo-1-piperidinyl)butanamide,-   2-[4-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[2-oxo-4-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl]butanamide,-   2-[2-oxo-4-(1-propynyl)-1-piperidinyl]butanamide,-   2-[4-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(1-butynyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(2, 2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(2-bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(2,2,2-trifluoroethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,-   2-(2-oxo-5-propyl-1-azepanyl)butanamide,-   2-[2-oxo-5-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,-   2-[5-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(azidomethyl)-2-oxo-1-azepanyl]butanamide,-   2-(2-oxo-5-phenyl-1-azepanyl)butanamide,-   2-[2-oxo-5-(2-thienyl)-1-azepanyl]butanamide,-   2-[2-oxo-5-(3-thienyl)-1-azepanyl]butanamide,-   2-[5-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,-   2-(5-ethynyl-2-oxo-1-azepanyl)butanamide,-   2-[5-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[2-oxo-5-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,-   2-[2-oxo-5-(1-propynyl)-1-azepanyl]butanamide,-   2-[5-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(1-butynyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,-   2-(2-oxo-6-propyl-1-azepanyl)butanamide,-   2-[2-oxo-6-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,-   2-[6-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(iodomethyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(azidomethyl)-2-oxo-1-azepanyl]butanamide,-   2-(2-oxo-6-phenyl-1-azepanyl)butanamide,-   2-[2-oxo-6-(2-thienyl)-1-azepanyl]butanamide,-   2-[2-oxo-6-(3-thienyl)-1-azepanyl]butanamide,-   2-[6-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(2, 2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,-   2-(6-ethynyl-2-oxo-1-azepanyl)butanamide,-   2-[6-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[2-oxo-6-(3, 3, 3-trifluoro-1-propynyl)-1-azepanyl]butanamide,-   2-[2-oxo-6-(1-propynyl)-1-azepanyl]butanamide,-   2-[6-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(1-butynyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(2, 2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,-   2-(2-oxo-4-propyl-1-azepanyl)butanamide,-   2-[2-oxo-4-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,-   2-[4-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(iodomethyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(azidomethyl)-2-oxo-1-azepanyl]butanamide,-   2-(2-oxo-4-phenyl-1-azepanyl)butanamide,-   2-[2-oxo-4-(2-thienyl)-1-azepanyl]butanamide,-   2-[2-oxo-4-(3-thienyl)-1-azepanyl]butanamide,-   2-[4-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(2, 2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(2, 2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,-   2-(4-ethynyl-2-oxo-1-azepanyl)butanamide,-   2-[4-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[2-oxo-4-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,-   2-[2-oxo-4-(1-propynyl)-1-azepanyl]butanamide,-   2-[4-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(1-butynyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:

-   (2S)-2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,-   (2S)-2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-(2-oxo-5-phenyl-1-piperidinyl]butanamide,-   (2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide.

iii) International Patent Application WO 2004/087658:

A compound having the formula I or a pharmaceutically acceptable saltthereof or stereoisomeric forms thereof,

wherein

R¹ is hydrogen,

R² is hydrogen or C1-20-alkyl,

R³ is hydrogen, C1-20-alkyl, C4-8-cycloalkyl, C5-8-cycloalkenyl, aryl,aromatic or non aromatic heterocycle, C1-20-alkoxy, or a group offormula —W—R⁸, R^(3a) is hydrogen, C1-20-alkyl or a group of formula:

or NR³R^(3a) is a group of formula

R⁴ is hydrogen,

R⁵ is hydrogen; nitro; halogen; azido; cyano; —S—C1-4-alkyl;—SO—C1-4-alkyl; —SO₂—C1-4-alkyl; —SONH₂; C1-20-alkyl unsubstituted orsubstituted by halogen; or C1-20-alkoxy unsubstituted or substituted byhalogen,

R⁶ is hydrogen, C1-20-alkyl or halogen,

R⁷ is hydrogen, C1-20-alkyl or halogen,

W is C1-12-alkylene, —NH— or —NHC(═O)—,

X is O, S or NH,

Y is O, S, —CR¹²R¹³—, —NR¹⁴— or —C(═O)—,

R⁸ is aryl or heterocycle,

R⁹, R¹⁰, R^(10a) and R¹¹ are independently selected from hydrogen,C1-4-alkyl, halogen, hydroxy or methoxycarbonyl,

or R10 and R^(10a) together form a C3-6-alkylene,

R¹² is hydrogen, C1-4-alkyl, halogen or hydroxy,

R¹³ is hydrogen,

or CR¹²R¹³ is dioxolanyl,

R¹⁴ is aryl, heterocycle or a group of formula —V—R¹⁵,

V is C₁₋₁₂-alkylene,

R¹⁵ is aryl or heterocycle,

m is 1 to 4,

n is 0 or 1,

and at least one of R⁵, R⁶ or R⁷ is different from hydrogen when R² ishydrogen, R³ is H or 2, 6-diisopropylphenyl, and R^(1a) is H.

In another aspect, the compound has the formula I or a pharmaceuticallyacceptable salt thereof or stereoisomeric forms thereof,

wherein

R¹ is hydrogen,

R² is hydrogen or C1-20-alkyl,

R³ is hydrogen, C1-20-alkyl, C4-8-cycloalkyl, C5-8-cycloalkenyl, aryl,aromatic or non aromatic heterocycle, C1-20-alkoxy, or a group offormula —W—R⁸,

R^(3a) is hydrogen, C1-20-alkyl or a group of formula:

or NR³R^(3a) is a group of formula

R⁴ is hydrogen,

R⁵ is hydrogen; nitro; halogen; C1-20-alkyl unsubstituted or substitutedby halogen; or C1-20-alkoxy unsubstituted or substituted by halogen,

R⁶ is hydrogen, C1-20-alkyl or halogen,

R⁷ is hydrogen, C1-20-alkyl or halogen,

W is C1-12-alkylene, —NH— or —NHC(═O)—,

X is O, S or NH,

Y is O, S, —CR¹²R¹³—, —NR¹⁴— or —C(═O)—,

R⁸ is aryl or heterocycle,

R⁹, R¹⁰, R^(10a) and R¹¹ are independently selected from hydrogen,C1-4-alkyl, halogen, hydroxy or methoxycarbonyl,

or R¹⁰ and R^(10a) together form a C3-6-alkylene,

R¹² is hydrogen, C1-4-alkyl, halogen or hydroxy,

R¹³ is hydrogen,

or CR¹²R¹³ is dioxolanyl,

R¹⁴ is aryl, heterocycle or a group of formula —V—R¹⁵,

V is C1-12-alkylene,

R¹⁵ is aryl or heterocycle,

m is 1 to 4,

n is 0 or 1,

and at least one of R⁵, R⁶ or R⁷ is different from hydrogen when R² ishydrogen, R³ is H or 2,6-diisopropylphenyl, and R^(3a) is H.

The term “alkyl”, as used herein, is defined as including saturated,monovalent hydrocarbon radicals having straight, branched or cyclicmoieties or combinations thereof and containing 1-20 carbon atoms,preferably 1-6 carbon atoms and more preferably 1-4 carbon atoms fornon-cyclic alkyl and 3-8 carbon atoms for cycloalkyl. Alliyl moietiesmay optionally be substituted by 1 to 5 substituents independentlyselected from halogen, hydroxy, alkoxy, alkoxycarbonyl, ester oralkylamino. Preferred alkyl groups are methyl, ethyl, n-propyl,isopropyl, trifluoromethyl, n-butyl, 2-fluoroethyl, 3-hydroxypropyl,3-hydroxy-2, 2-dimethylpropyl, 1-(hydroxymethyl) propyl, 3,3,3-trifluoro-2-hydroxypropyl, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl and3-(dimethylamino) propyl.

The term “cycloalkyl”, as used herein, refers to a monovalent group of 3to 18 carbon atoms, preferably 4-8 carbon atoms, derived from asaturated cyclic or polycyclic hydrocarbon which may be substituted byany suitable group including but not limited to one or more moietiesselected from groups as described above for the alkyl groups. Preferredcycloalkyl group is cycloheptyl.

The term “alkylene”, as used herein, represents a divalent alkyl group,having straight or branched moieties, containing 1-12 carbon atoms,preferably 1-6 carbon atoms, and being optionally substituted with anysuitable group, including but not limited to one or more moietiesselected from groups as described above for the alkyl groups. Preferredalkylene groups are methylene, ethylene, hydroxyethylene, trimethyleneor propylene.

The term “cycloalkenyl”, as used herein, is defined as a cyclicunsaturated hydrocarbon radical having at least one double bond,containing 4-20 carbon atoms, preferably 5-8 carbon atoms, and beingoptionally substituted with any suitable group, including but notlimited to one or more moieties selected from groups as described abovefor the alkyl groups. Preferred cycloalkenyl group is 6-(hydroxymethyl)cyclohex-3-en-1-yl.

The term “aryl”, as used herein, is defined as including an organicradical derived from an aromatic hydrocarbon consisting of 1-3 rings andcontaining 6-30 carbon atoms by removal of one hydrogen, such as phenyland naphthyl each optionally substituted by 1 to 5 substituentsindependently selected from halogen, hydroxy, nitro, C1-6-alkyl,C1-6-alkoxy, C1-6-alkylsulfonyl, trifluoromethylthio or pyridinylalkyl.Aryl radicals are preferably phenyl radicals. Preferred aryl groups arephenyl, 3-hydroxyphenyl, 3-fluorophenyl, 3-methylphenyl, 4-methylphenyl,4-hydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 3-(2-pyridin-2-ylethyl)phenyl, 3,4-dimethylphenyl, 4-tert-butylphenyl, 4-methylsulfonylphenyl,2-nitrophenyl, 2-chloro-6-fluorophenyl, 2-[(trifluoromethyl) thio]phenyl, 2-chlorophenyl or 4-bromophenyl.

The term “halogen”, as used herein, includes an atom of Cl, Br, F, I.

The term “nitro”, as used herein, represents a group of the formula—NO₂.

The term “hydroxy”, as used herein, represents a group of the formula—OH.

The term “alkoxy”, as used herein, represents a group of formula —OR^(b)wherein R^(b) is an alkyl group, as defined above.

The term “ester”, as used herein, represents a group of formula—COOR^(C) wherein R^(c) is an alkyl group or an aryl group, as definedabove.

The term “alkoxycarbonyl”, as used herein, represents a group of formula—COOR^(d) wherein R^(d) is an alkyl group, as defined above.

The term “amino”, as used herein, represents a group of the formula—NH₂.

The term “alkylamino”, as used herein, represents a group of formula—NHR^(e) or —NR^(e)R^(f) wherein R^(e) and R^(f) are alkyl group asdefined above.

The term alkylsulfonyl, as used herein is defined as representing agroup of formula —SO₂—R^(g), wherein R^(g) is C1-4-alkyl.

The term “heterocycle”, as used herein is defined as including anaromatic or non aromatic cycloalkyl or cycloalkenyl moiety as definedabove, having at least one O, S and/or N atom interrupting thecarbocyclic ring structure and optionally, one of the carbon of thecarbocyclic ring structure may be replaced by a carbonyl.

Non-limiting examples of aromatic heterocycles are pyrazolyl, furyl,imidazolyl, triazolyl, oxazolyl, pyridinyl, pyrrolyl, thienyl,isothiazolyl, benzimidazolyl, tetrazolyl, isooxazolyl, oxazolyl,thiazolyl, 1,2, 4-thiadiazolyl, oxadiazole, pyridazinyl, pyrimidinyl,pyrazinyl, isoindolyl, triazolopyridinyl, imidazolopyridinyl,pyrrolopyrimidinyl, pyrazolopyrimidinyl, quinazolinyl, quinolizinyl,naphthyridinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl,indolyl, indolizinyl, purinyl, carbazolyl, thieno (2,3-b) furanyl,thianthrenyl, benzothiazolyl, benzoxazolyl, cinnolinyl, quinoxalinyl,phenothiazinyl, isochromanyl and xanthenyl, optionally substituted by 1to 5 substituents independently selected from halogen, hydroxy, thiol,amino, nitro, cyano, azido, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkyl,C1-6-haloalkyl, formyl or ester. More preferred aromatic heterocyclesare pyrazolyl, furyl, imidazolyl, triazolyl, oxazolyl and pyridinyl.

Non-limiting examples of non aromatic heterocycles aretetrahydrofuranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl,morpholinyl, thiomorpholinyl, pyrrolidinyl, thiazolidinyl, indolinyl,tetrahydrobenzazocinyl, dihydroisochromenyl, tetrahydropyranyl,oxooctahydroquinolinyl, dioxolanyl, 1-oxaspiro (4.5) dec-2-yl,pyrrolidinyl, 2-oxo-pyrrolidinyl, 8-thiabicyclo [3.2.1] cyclooctanyl,1,4-dithiepanyl, tetrahydro-2H-thiopyranyl, azepanyl and azocanyl,optionally substituted by 1 to 5 substituents independently selectedfrom halogen, hydroxy, thiol, amino, nitro, cyano, azido, C1-6-alkoxy,C1-6-alkylthio, C1-6-alkyl, C1-6-haloalkyl, formyl or ester. Morepreferred non aromatic heterocycles are tetrahydrofuranyl, piperidinyl,piperidyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl,pyrrolidinyl, thiazolidinyl, indolinyl, tetrahydro-1-benzazocin-1(2H)-yl, 3, 4-dihydro-1H-isochromen-1-yl, tetrahydropyranyl,oxooctahydroquinolinyl and dioxolanyl. The term “heterocycle” alsoincludes bicyclic, tricyclic and tetracyclic, spiro groups in which anyof the above heterocyclic rings is fused to one or two ringsindependently selected from an aryl ring, a cycloalkyl ring, acycloalkenyl ring or another monocyclic heterocyclic ring or where amonocyclic heterocyclic group is bridged by an alkylene group, such asquinuclidinyl, 7-azabicyclo (2.2.1)heptanyl, 7-oxabicyclo(2.2.1)heptanyl and 8-azabicyclo (3.2.1)octanyl.

The term “pyridinylalkyl”, as used herein, represents a group of formula—R^(h)— pyridinyl in which R^(h) is C1-4-alkylene.

The term “azido” as used herein, represents a group of the formula —N₃.

The term “cyano” as used herein, represents a group of the formula —CN.

Generally, R² is hydrogen or C1-4-alkyl.

Preferably, R² is hydrogen, methyl or ethyl. More preferably, R² ishydrogen or methyl.

Generally, R³ is hydrogen; C1-6-alkyl unsubstituted or substituted by 1to 5 substituents selected from halogen, hydroxy, alkoxy, alkoxycarbonylor alkylamino; C5-7-cycloalkyl; (hydroxymethyl) cyclohexenyl; phenylunsubstituted or substituted by 1 to 5 substituents selected fromhalogen, C1-4-alkyl, hydroxy, methoxy, nitro, methylsulfonyl,trifluoromethylthio or pyridinylalkyl; pyridinyl unsubstituted orsubstituted by methoxy; triazolyl; C1-4-alkoxy; or a group of formula—W—R⁸ wherein:

Generally, W is C1-4-alkylene unsubstituted or substituted by halogen,hydroxy, C1-4-alkyl or alkoxy; —NH—; or —NHC(═O)—; and

R⁸ is phenyl unsubstituted or substituted by 1 to 5 substituentsselected from halogen, C1-4-alkyl, hydroxy, methoxy, nitro,methylsulfonyl or trifluoromethylthio; furyl unsubstituted orsubstituted by methyl; pyrazolyl; pyridinyl; morpholinyl;tetrahydrobenzazocinyl; piperidinyl unsubstituted or substituted bymethyl; dihydroisochromenyl or dihydroimidazolyl.

Preferably, R³ is hydrogen, n-butyl, cycloheptyl, 2-fluoroethyl,3-hydroxypropyl, 3-hydroxy-2, 2-dimethylpropyl, 1-(hydroxymethyl)propyl, 3,3, 3-trifluoro-2-hydroxypropyl, 3-ethoxypropyl,2-ethoxy-2-oxoethyl, 3-(dimethylamino) propyl, 6-(hydroxymethyl)cyclohex-3-en-1-yl, 3-hydroxyphenyl, 3-fluorophenyl,3-(2-pyridin-2-ylethyl) phenyl, 3, 4-dimethylphenyl, 4-tert-butylphenyl,benzyl, 4-hydroxy-3-methoxybenzyl, 4-methylsulfonylbenzyl,2-nitrobenzyl, 2-chloro-6-fluorobenzyl, 2-[(trifluoromethyl) thio]benzyl, 2-hydroxy-2-phenylethyl, 2-(3,4-dimethoxyphenyl) ethyl,2-(2-chlorophenyl) ethyl, 2-(4-methylphenyl) ethyl, (4-bromophenyl)amino, pyridin-3-yl, 6-methoxypyridin-3-yl, 4H-1, 2, 4-triazol-3-yl,pyridin-4-ylmethyl, (5-methyl-2-furyl) methyl,3-(1H-pyrazol-1-yl)propyl, 2-morpholin-4-ylethyl, 2-((3, 4,5,6-tetrahydro-1-benzazocin-1 (2H)-yl) propyl, 2-(2-methylpiperidin-1-yl)ethyl, 3, 4-dihydro-1H-isochromen-1-ylmethyl, methoxy,(4-pyridinylcarbonyl) amino or 4, 5-dihydro-1H-imidazol-2-ylamino. Morepreferably, R³ is hydrogen.

Generally, R^(3a) is hydrogen, C1-4-alkyl or a group of formula

wherein m is 1 to 4.

Preferably, R^(3a) is hydrogen, methyl or tetrahydrofuran-2-ylmethyl.More preferably, R^(3a) is hydrogen.

In another embodiment, NR³R^(3a) is piperidinyl unsubstituted orsubstituted by hydroxy; thiomorpholinyl; thiazolidinyl unsubstituted orsubstituted by C1-4-alkoxycarbonyl; 2, 5-dihydro-1H-pyrrol-1-yl; 1,4-dioxa-8-azaspiro [4.5] dec-8-yl; 4-oxooctahydro-1(2H)-quinolinyl; or agroup of formula

wherein R¹⁴ is pyridinyl; phenyl unsubstituted or substituted byhalogen, hydroxy, C1-4-alkyl; or a group of formula —V—R¹⁵ wherein V isunsubstituted C1-4-alkylene and R¹⁵ is phenyl or morpholinyl.

In a preferred embodiment, NR³R^(3a) is 4-pyridin-2-ylpiperazin-1-yl,4-(3-methylphenyl) piperazin-1-yl, 4-(4-hydroxyphenyl) piperazin-1-yl,4-(2-phenylethyl) piperazin-1-yl, 4-(2-morpholin-4-ylethyl)piperazin-1-yl, 3-hydroxypiperidin-1-yl, thiomorpholin-4-yl,4-methoxycarbonyl-1,3-thiazolidin-3-yl, 2, 5-dihydro-1H-pyrrol-1-yl, 1,4-dioxa-8-azaspiro [4.5] dec-8-yl or 4-oxooctahydro-1(2H)-quinolinyl.

Generally, R⁵ is hydrogen, nitro, halogen, C1-4-alkyl, unsubstituted orsubstituted by halogen, or C1-4-alkoxy unsubstituted or substituted byhalogen.

Preferably, R⁵ is hydrogen, methyl, ethyl, trifluoromethyl,trifluoromethoxy, n-propyl, isopropyl, nitro, or halogen. Morepreferably, R⁵ is halogen or trifluoromethyl.

Generally, R⁶ is hydrogen, C1-6-alkyl or halogen.

Preferably, R⁶ is hydrogen, methyl or Cl. More preferably, R⁶ ishydrogen.

Generally, R⁷ is hydrogen, methyl or halogen.

Preferably, R⁷ is hydrogen, methyl, Br, F or Cl. More preferably, R⁷ ishydrogen, Br or F.

Combinations of one or more of these preferred compound groups areespecially preferred.

In a preferred embodiment, the compound has the formula I or apharmaceutically acceptable salt thereof or stereoisomeric formsthereof,

wherein R¹ is hydrogen,

R² is hydrogen or C1-4-alkyl,

R³ is hydrogen; C1-6-alkyl unsubstituted or substituted by 1 to 5substituents selected from halogen, hydroxy, alkoxy, alkoxycarbonyl oralkylamino; C5-7-cycloalkyl; (hydroxymethyl) cyclohexenyl; phenylunsubstituted or substituted by 1 to 5 substituents selected fromhalogen, C1-4-alkyl, hydroxy, methoxy, nitro, methylsulfonyl,trifluoromethylthio or pyridinylalkyl; pyridinyl unsubstituted orsubstituted by methoxy; triazolyl; C1-4-alkoxy; or a group offormula-W—R⁸,

R^(3a) is hydrogen, C1-4-alkyl or a group of formula

or NR³R^(3a) is piperidinyl unsubstituted or substituted by hydroxy;thiomorpholinyl; thiazolidinyl unsubstituted or substituted byC1-4-alkoxycarbonyl; 2,5-dihydro-1H-pyrrol-1-yl; 1,4-dioxa-8-azaspiro[4.5] dec-8-yl; 4-oxooctahydro-1(2H)-quinolinyl; or a group of formula

R⁴ is hydrogen,

R⁵ is hydrogen; nitro; halogen; C1-4-alkyl, unsubstituted or substitutedby halogen; or C1-4-alkoxy unsubstituted or substituted by halogen,

R6 is hydrogen, C1-6-allyl or halogen,

R7 is hydrogen, methyl or halogen,

W is C1-4-alkylene unsubstituted or substituted by halogen, hydroxy,C1-4-alkyl or alkoxy; —NH—; or —NHC(═O)—,

R8 is phenyl unsubstituted or substituted by 1 to 5 substituentsselected from halogen, C1-4-alkyl, hydroxy, methoxy, nitro,methylsulfonyl or trifluoromethylthio; furyl unsubstituted orsubstituted by methyl; pyrazolyl; pyridinyl; morpholinyl;tetrahydrobenzazocinyl; piperidinyl unsubstituted or substituted bymethyl; dihydroisochromenyl or dihydroimidazolyl,

R¹⁴ is pyridinyl; phenyl unsubstituted or substituted by halogen,hydroxy, C1-4-alkyl; or a group of formula-V—R¹⁵,

V is unsubstituted C1-4-alkylene,

R¹⁵ is phenyl or morpholinyl,

m is 1 to 4,

and at least one of R⁵, R⁶ or R⁷ is different from hydrogen when R² ishydrogen, R³ is H or 2,6-diisopropylphenyl, and R^(3a) is H.

In a more preferred embodiment, the compound has the formula I or apharmaceutically acceptable salt thereof or stereoisomeric formsthereof,

wherein

R¹ is hydrogen,

R² is hydrogen, methyl or ethyl,

R³ is hydrogen, n-butyl, cycloheptyl, 2-fluoroethyl, 3-hydroxypropyl,3-hydroxy-2,2-dimethylpropyl, 1-(hydroxymethyl) propyl, 3,3,3-trifluoro-2-hydroxypropyl, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl,3-(dimethylamino) propyl, 6-(hydroxymethyl) cyclohex-3-en-1-yl,3-hydroxyphenyl, 3-fluorophenyl, 3-(2-pyridin-2-ylethyl) phenyl,3,4-dimethylphenyl, 4-tert-butylphenyl, benzyl,4-hydroxy-3-methoxybenzyl, 4-methylsulfonylbenzyl, 2-nitrobenzyl,2-chloro-6-fluorobenzyl, 2-[(trifluoromethyl)thio] benzyl,2-hydroxy-2-phenylethyl, 2-(3, 4-dimethoxyphenyl) ethyl,2-(2-chlorophenyl) ethyl, 2-(4-methylphenyl) ethyl, (4-bromophenyl)amino, pyridin-3-yl, 6-methoxypyridin-3-yl, 4H-1,2,4-triazol-3-yl,pyridin-4-ylmethyl, (5-methyl-2-furyl) methyl, 3-(1H-pyrazol-1-yl)propyl, 2-morpholin-4-ylethyl, 2-((3, 4,5, 6-tetrahydro-1-benzazocin-1(2H)-yl) propyl, 2-(2-methylpiperidin-1-yl) ethyl, 3,4-dihydro-1H-isochromen-1-ylmethyl, methoxy, (4-pyridinylcarbonyl) aminoor 4, 5-dihydro-1H-imidazol-2-ylamino,

R^(3a) is hydrogen, methyl or tetrahydrofuran-2-ylmethyl, or NR³R^(3a)4-pyridin-2-ylpiperazin-1-yl, 4-(3-methylphenyl) piperazin-1-yl,4-(4-hydroxyphenyl) piperazin-1-yl, 4-(2-phenylethyl) piperazin-1-yl,4-(2-morpholin-4-ylethyl) piperazin-1-yl, 3-hydroxypiperidin-1-yl,thiomorpholin-4-yl, 4-methoxycarbonyl-1, 3-thiazolidin-3-yl, 2,5-dihydro-1H-pyrrol-1-yl, 1,4-dioxa-8-azaspiro [4.5]dec-8-yl or4-oxooctahydro-1(2H)-quinolinyl,

R⁴ is hydrogen,

R⁵ is hydrogen, methyl, ethyl, trifluoromethyl, trifluoromethoxy,n-propyl, isopropyl, nitro or halogen,

R⁶ is hydrogen, methyl or Cl,

R⁷ is hydrogen, methyl, Br, F or Cl,

and at least one of R⁵, R⁶ or R⁷ is different from hydrogen when R² ishydrogen, R³ is H or 2,6-diisopropylphenyl, and R^(3a) is H.

More preferably, R² is hydrogen or methyl, R³ is hydrogen, R^(3a) ishydrogen, R⁵ is halogen or trifluoromethyl, R⁶ is hydrogen and R⁷ ishydrogen, Br or F.

In all the above-mentioned scopes, when R² is C1-20-alkyl, the carbonatom to which R² is attached is preferably in the “S”-configuration.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:2-(5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide;2-(5-chloro-2-oxo-2, 3-dihydro-1H-indol-1-yl) acetamide; 2-(5,7-dibromo-2-oxo-2, 3-dthydro-1H-indol-1-yl) acetamide;2-(5-nitro-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide;2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide;2-(5-chloro-2-oxo-2, 3-dihydro-1H-indol-1-yl) propanamide;(2R)-2-(5-chloro-2-oxo-2, 3-dihydro-1H-indol-1-yl) propanamide;(2S)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) propanamide;2-[2-oxo-5-(trifluoromethoxy)-2, 3-dihydro-1H-indol-1-yl] acetamide;2-(5-isopropyl-2-oxo-2, 3-dihydro-1H-indol-1-yl)acetamide;2-(5-ethyl-2-oxo-2, 3-dihydro-1H-indol-1-yl) acetamide;2-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide;2-(5,7-dimethyl-2-oxo-2, 3-dihydro-1H-indol-1-yl) acetamide;2-(5-bromo-2-oxo-2, 3-dihydro-1H-indol-1-yl) acetamide;2-(2-oxo-5-propyl-2, 3-dihydro-1H-indol-1-yl) acetamide;2-[2-oxo-5-(trifluoromethyl)-2, 3-dihydro-1H-indol-1-yl] acetamide;2-(5, 6-dimethyl-2-oxo-2, 3-dihydro-1H-indol-1-yl) acetamide;2-(7-chloro-2-oxo-2, 3-dihydro-IH-indol-1-yl) acetamide;2-(6-chloro-2-oxo-2, 3-dihydro-IH-indol-1-yl) acetamide;2-(5-chloro-2-oxo-2, 3-dihydro-1H-indol-1-yl) butanamide;(+)-2-(5-chloro-2-oxo-2, 3-dihydro-1H-indol-1-yl) butanamide;(−)-2-(5-chloro-2-oxo-2, 3-dihydro-IH-indol-1-yl) butanamide;2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide;(+)-2-(5-methyl-2-oxo-2, 3-dihydro-1H-indol-1-yl) propanamide;(−)-2-(5-methyl-2-oxo-2, 3-dihydro-1H-indol-1-yl) propanamide;2-(5-bromo-2-oxo-2,3-dihydro-1H-indol-1-yl) propanamide;(−)-2-(5-bromo-2-oxo-2, 3-dihydro-1H-indol-1-yl) propanamide;(+)-2-(5-bromo-2-oxo-2, 3-dihydro-1H-indol-1-yl) propanamide;2-(5-chloro-7-fluoro-2-oxo-2, 3-dihydro-1H-indol-1-yl) acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxyphenyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-fluorophenyl) acetamide;2-(5-chloro-2-oxo-2, 3-dihydro-1H-indol-1-yl)-N-[3-(2-pyridin-2-ylethyl)phenyllacetarnide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[6-(hydroxymethyl)cyclohex-3-en-1-yl]acetanuide;5-chloro-1-[2-oxo-2-(4-pyridin-2-ylpiperazin-1-yl) ethyl3-1,3-dihydro-2H-indol-2-one; 5-chloro-1-{2-[4-(3-methylphenyl)piperazin-1-yl]-2-oxoethyl}-1, 3-dihydro-2H-indol-2-one;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(4-hydroxy-3-methoxybenzyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(pyridin-4-ylmethyl)-N-(tetrahydrofuran-2-ylmethyl)acetamide;5-chloro-1-[2-(3-hydroxypiperidin-1-yl)-2-oxoethyl]-1,3-dihydro-2H-indol-2-one;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N′-isonicotinoylacetohydrazide;5-chloro-1-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3-dihydro-2H-indol-2-one;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(4H-1, 2, 4-triazol-3-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[4-(methylsulfonyl) benzyl] acetamide;1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) acetyl]octahydroquinolin-4 (1H)-one; N′-(4-bromophenyl)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) acetohydrazide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(6-methoxypyridin-3-yl)acetamide; N-butyl-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxypropyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[3-(dimethylamino)propyl] acetamide; 5-chloro-1-{2-oxo-2-[4-(2-phenylethyl)pperazin-1-yl]ethyl}-1, 3-dihydro-2H-indol-2-one; ethyl {[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) acetyl]amino}acetate;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-ethoxypropyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-fluoroethyl) acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-methoxy-N-methylacetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3, 4-dimethylphenyl)acetamide; N-(4-tert-butylphenyl)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxy-2, 2-dimethylpropyl) acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[1-(hydroxymethyl)propyl] acetamide; 2-(5-chloro-2-oxo-2, 3-dihydro-1H-indol-1-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl) acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-hydroxy-2-phenylethyl) acetamide;5-chloro-1-{2-[4-(4-hydroxyphenyl) piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-one; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(pyridin-4-ylmethyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[(5-methyl-2-furyl)methyl]acetamide;2-(5-chloro-2-oxo-2, 3-dihydro-1H-indol-1-yl)-N-[3-(1H-pyrazol-1-yl)propyl] acetamide; methyl 3-[(5-chloro-2-oxo-2, 3-dihydro-1H-indol-1-yl]acetyl]-1, 3-thiazolidine-4-carboxylate; 5-chloro-1-[2-(2,5-dihydro-1H-pyrrol-1-yl)-2-oxoethyl]-1, 3-dihydro-2H-indol-2-one;2-(5-chloro-2-oxo-2, 3-dihydro-1H-indol-1-yl)-N′-(4,5-dihydro-1H-imidazol-2-yl) acetohydrazide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(3, 4-dimethoxyphenyl) ethyl] acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(2-chlorophenyl)etl-lyllacetaniide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(4-methylphenyl)ethyl] acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-morpholin-4-ylethyl)acetamide; 2-(5-chloro-2-oxo-2, 3-dihydro-1H-indol-1-yl)-N-[2-(3,4, 5,6-tetrahydro-1-benzazocin-1 (2H)-yl) propyl] acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(2-methylpiperidin-1-yl) ethyl] acetamide;2-(5-chloro-2-oxo-2, 3-dihydro-1H-indol-1-yl)-N-(2-nitrobenzyl)acetamide; 2-(5-chloro-2-oxo-2, 3-dihydro-1H-indol-1-yl)-N-(3,4-dihydro-1H-isochromen-1-ylinethyl) acetamide;N-(2-chloro-6-fluorobenzyl)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide; N-benzyl-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-methylacetamide; 2-(5-chloro-2-oxo-2,3-dthydro-1H-indol-1-yl)-N-{2-[(trifluoromethyl) thio] benzyl}acetamide; 5-chloro-1-[2-(1, 4-dioxa-8-azaspiro [4.5]dec-8-yl)-2-oxoethyl]-1, 3-dihydro-2H-indol-2-one; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-cycloheptylacetamide;5-chloro-1-{2-[4-(2-morpholin-4-ylethyl) piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-one; and2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-pyridin-3-ylacetamide.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:2-(5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide;2-(5-chloro-2-oxo-2, 3-dihydro-1H-indol-1-yl) acetamide; 2-(5,7-dibromo-2-oxo-2, 3-dihydro-1H-indol-1-yl)acetamide;(2S)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) propanamide;2-[2-oxo-5-(trifluoromethyl)-2, 3-dihydro-1H-indol-1-yl] acetamide and2-(5-chloro-7-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide.

In another embodiment, compounds useful in the methods and compositionsof this invention are selected from the group consisting of:2-(5-chloro-2-oxo-2, 3-dihydro-1H-indol-1-yl) acetamide and(2S)-2-(5-chloro-2-oxo-2, 3-dihydro-1H-indol-1-yl) propanamide.

iv) U.S. Pat. No. 7,244,747:

A compound having the formula I or a pharmaceutically acceptable saltthereof,

wherein R¹ is hydrogen, C₁₋₂₀ alkyl, C₃₋₈ cycloalkyl, halogen, hydroxy,alkoxy, aryloxy, ester, amido, cyano, nitro, amino, guanidine, aminoderivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl,alkylsulfinyl, arylsulfinyl, aryl or heterocycle;

R² is hydrogen, C₁₋₂₀ alkyl, alkoxy, amino, halogen, hydroxy, ester,amido, nitro, cyano, carbamate, or aryl;

R³ is hydrogen, C₁₋₂₀ alkyl, alkoxy, amino, halogen, hydroxy, ester,amido, nitro, cyano, carbamate, or aryl;

or R² and R³ can form together with the imidazole ring the following1H-benzimidazole cycle

R⁴ is hydrogen, C₁₋₂₀ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, aryl, azido,alkoxycarbonylamino, arylsulfonyloxy or heterocycle;

R^(4a) is hydrogen or C₁₋₂₀ alkyl;

or R⁴ and R^(4a) can form together a C₃₋₈ cycloalkyl;

R⁵ is hydrogen;

or R⁴, R^(4a) and R⁵ can form together with the 2-oxo-1-pyrrolidine ringthe following 1,3-dihydro-2H-indol-2-one cycle

R⁶ is hydrogen or C₁₋₂₀ alkyl;

R⁷ is hydrogen;

or R⁶ and R⁷ are linked together to form a C₃₋₆ cycloalkyl;

R⁸ is hydrogen, halogen, nitro, cyano, C₁₋₂₀ alkyl or alkoxy;

R⁹ is hydrogen, C₁₋₂₀ alkyl, halogen, hydroxy, alkoxy, aryloxy, ester,amido, cyano, nitro, amino, amino derivative, alkylthio, arylthio,alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl;

R¹⁰ is hydrogen, C₁₋₂₀ alkyl, halogen, hydroxy, alkoxy, aryloxy, ester,amido, cyano, nitro, amino, amino derivative, alkylthio, arylthio,alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl;

R¹¹ is hydrogen, halogen, nitro, cyano, C₁₋₂₀ alkyl or alkoxy;

R¹² is hydrogen or halogen;

R¹³ is hydrogen, nitro, halogen, heterocycle, amino, aryl, C₁₋₂₀ alkylunsubstituted or substituted by halogen, or alkoxy unsubstituted orsubstituted by halogen;

R¹⁴ is hydrogen, C₁₋₂₀ alkyl or halogen;

R¹⁵ is hydrogen, C₁₋₂₀ alkyl or halogen;

with the proviso that R⁴ is different from hydrogen when represents agroup of formula

The asterisk * indicates the point of attachment of the substituents.

In a preferred embodiment, the compounds have the formula I, theirtautomers, geometrical isomers (including cis and trans, Z and Eisomers), enantiomers, diastereoisomers and mixtures thereof (includingall possible mixtures of stereoisomers), or pharmaceutically acceptablesalts thereof,

wherein R¹ is hydrogen, C₁₋₂₀ alkyl, C₃₋₈ cycloalkyl, halogen, hydroxy,ester, amido, cyano, nitro, amino, guanidine, alkylthio, alkylsulfonyl,alkylsulfinyl, aryl or heterocycle;

R² is hydrogen, C₁₋₂₀ alkyl, halogen, cyano, ester, carbamate or amido;

R³ is hydrogen, cyano, C₁₋₂₀ alkyl, halogen or ester;

or R² and R³ can form together with the imidazole ring the following1H-benzimidazole cycle

R⁴ is hydrogen, C₁₋₂₀ alkyl, C₂₋₁₂ alkenyl or aryl;

R^(4a) is hydrogen;

R⁵ is hydrogen;

or R⁴, R^(4a) and R⁵ can form together with the 2-oxo-1-pyrrolidine ringthe following 1,3-dihydro-2H-indol-2-one cycle

R⁶ is hydrogen or C₁₋₂₀ alkyl;

R⁷ is hydrogen; or R⁶ and R⁷ are linked together to form a C₃₋₆cycloalkyl;

R⁸ is hydrogen;

R⁹ is hydrogen, C₁₋₂₀ alkyl, halogen or alkoxy;

R¹⁹ is hydrogen, C₁₋₂₀ alkyl, halogen or cyano;

R¹¹ is hydrogen;

R¹² is hydrogen or halogen;

R¹³ is hydrogen, halogen, heterocycle or C₁₋₂₀ alkyl;

R¹⁴ is hydrogen;

R¹⁵ is hydrogen;

with the proviso that R⁴ is different from hydrogen when

represents a group of formula

The term “alkyl”, as used herein, represents saturated, monovalenthydrocarbon radicals having straight (unbranched) or branched or cyclicor combinations thereof and containing 1-20 carbon atoms, preferably1-10 carbon atoms, more pre preferred alkyl groups have 1-3 carbonatoms. Alkyl moieties may optionally be substituted by 1 to 5substituents independently selected from the group consisting ofhalogen, hydroxy, cyano, azido, aryloxy, alkoxy, alkythio,alkanoylamino, arylcarbonylamino, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl or aryl. Usually alkyl groups, in the presentcase, are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl,1-ethylpropyl, n-heptyl, 2,4,4-trimethylpentyl, n-decyl, chloromethyl,trifluoromethyl, 2-bromo-2,2-difluoroethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoropropyl, hydroxymethyl, cyanomethyl, azidomethyl,(acetylamino)methyl, (propionylamino)methyl, (benzoylamino)methyl,(4-chlorophenoxy)methyl, benzyl, 2-phenylethyl or 2-(methylthio)ethyl.Preferred alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, t-butyl, 1-ethylpropyl, 2,4,4-trimethylpentyl, chloromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, cyanomethyl,azidomethyl, (acetylamino)methyl, (propionylamino)methyl,(benzoylamino)methyl or 2-(methylthio)ethyl. More preferred alkyl groupsare methyl, ethyl, n-propyl, propyl, n-butyl, azidomethyl ortrifluoromethyl. Most preferred alkyl groups are methyl or n-propyl.

The term “cycloalkyl”, as used herein, represents a monovalent group of3 to 8 carbon atoms, usually 3-6 carbon atoms derived from a saturatedcyclic hydrocarbon, which may be substituted by any suitable groupincluding but not limited to one or more moieties selected from groupsas described above for the alkyl groups. Preferred cycloalkyl groups arecyclopropyl and cyclohexyl.

The term “alkenyl” as used herein, represents straight, branched orcyclic unsaturated hydrocarbon radicals or combinations thereof havingat least one carbon-carbon double bond, containing 2-12 carbon atoms,preferably usually 2-4 carbon atoms. Alkenyl groups are being optionallysubstituted with any suitable group, including but not limited to one ormore moieties selected from groups as described above for the alkylgroups. Usually an alkenyl group is ethenyl (vinyl) optionallysubstituted by 1 to 3 halogens. Preferred alkenyl group, in the presentcase, is 2, 2-difluorovinyl.

The term a “alkynyl” as used herein, represents straight, branched orcyclic hydrocarbon radicals or combinations thereof containing at leastone carbon-carbon triple bond, containing 2-12 carbon atoms, preferably2-6 carbon atoms, and being optionally substituted by any suitablegroup, including but not limited to one or more moieties selected fromgroups as described above for the alkyl groups. Preferably an alkynylgroup is a halogenoalkynyl group (haloalkynyl group).

Groups qualified by prefixes such as “s”, “i”, “t” and the like (e.g.“i-propyl”, “s-butyl”) are branched derivatives.

The term “aryl” as used herein, is defined as phenyl optionallysubstituted by 1 to 4 substituents independently selected from halogen,cyano, alkoxy, alkylthio, C₁₋₃ alkyl or azido, preferably halogen orazido. Usually aryl groups, in the present case are phenyl,3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl,2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl,3,4,5-trifluorophenyl, 3-azido-2,4-difluorophenyl or3-azido-2,4,6-trifluorophenyl. Preferably, aryl groups are phenyl,3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl,2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl,3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. Most preferred arylgroups are phenyl, 3-chlorophenyl, 3-fluorophenyl, 3,5-difluorophenyl,2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl,3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl.

The term “heterocycle”, as used herein, is defined as including anaromatic or non aromatic cycloalkyl moiety as defined above, having atleast one 0, S and/or N atom interrupting the carbocyclic ringstructure. Heterocyclic ring moieties can be optionally substituted byalkyl groups or halogens and optionally, one of the carbon of thecarbocyclic ring structure may be replaced by a carbonyl. Usuallyheterocycles are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-tetrahydrofuranyl, 1H-pyrrol-2-yl,1-methyl-1H-pyrrol-2-yl, 1H-pyrazol-2-yl, 1H-pyrazol-3-yl,4-chloro-1-methyl-1H-pyrazol-3-yl,5-chloro-1,3-dimethyl-1H-pyrazol-4-yl, 1,2,3-thiadiazol-4-yl,3,5-dimethyl-4-isothiazyl, 1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl,4-methyl-1H-imidazol-5-yl, or 2-methyl-1,3-thiazol-4-yl. Preferredheterocycles are 1H-imidazol-2-yl, 1,2,3-thiadiazol-4-yl,1H-pyrazol-3-yl, 2-furyl, 3-furyl, 2-thienyl, 1-methyl-1H-pyrrol-2-yl,1H-pyrrol-2-yl.

The term “halogen”, as used herein, includes an atom of chlorine,bromine, fluorine, iodine. Usually halogens are chlorine, bromine andfluorine. Preferred halogens are fluorine, bromine and chlorine.

The term “hydroxy”, as used herein, represents a group of formula —OH.

The term “alkoxy”, as used herein, represents a group of formula —OR^(a)

wherein R^(a) is an alkyl group, as defined above. Preferred alkoxygroup is methoxy.

The term “aryloxy”, as used herein, represents a group of formula—OR^(b) wherein R^(b) is an aryl group, as defined above. Preferredaryloxy group is phenoxy.

The term “ester”, as used herein, represents a group of formula—COOR^(c) wherein R^(c) is an alkyl group or aryl group, as definedabove. Preferred ester group is methoxycarbonyl.

The term “amido”, as used herein, represents a group of formula —CONH₂.

The term “amino”, as used herein, represents a group of formula —NH₂.

The term “aminoderivative”, as used herein, represents an alkylamino oran arylamino group, wherein the terms “alkyl” and “aryl” are defined asabove.

The term “cyano”, as used herein, represents a group of formula —CN.

The term “nitro”, as used herein, represents a group of formula NO₂.

The term “azido”, as used herein, represents a group of formula —N₃.

The term “guanidine”, as used herein, represents a group of formula—NHC(═NH)NH₂.

The term “alkylthio”, as used herein, represents a group of formula—SR^(d) wherein R^(d) is an alkyl group, as defined above. Preferredalkylthio group is methylthio.

The term “alkylsulfonyl”, as used herein, represents a group of formula—S(═O)₂R^(e) wherein R^(e) is an alkyl group, as defined above.Preferred alkylsulfonyl group is methylsulfonyl.

The term “alkylsulfinyl”, as used herein, represents a group of formula—S(═O)R^(f) wherein R^(f) is an alkyl group, as defined above. Preferredalkylsulfinyl group is methylsulfinyl.

The term “arylthio”, as used herein, represents a group of formula—SR^(g) wherein R^(g) is an aryl group, as defined above.

The term “arylsulfonyl”, as used herein, represents a group of theformula —S(═O)₂R^(h) wherein R^(h) is an aryl group, as defined above.

The term “arylsulfinyl”, as used herein, represents a group of theformula —S(═O)R^(i) wherein R^(i) is an aryl group, as defined above.

The term “carbamate” as used herein, represents a group of formula—N(H)C(O)OR^(j), wherein R^(j) is an alkyl or an aryl, as defined above.Usually carbamate groups are (propoxycarbonyl)amino or(benzyloaxycarbonyl)amino. Preferred carbamate group is(benzyloaxycarbonyl)amino.

The term “alkanoylamino” as used herein, represents a group of theformula —NHC(═O)R^(k) wherein R^(k) is an alkyl group, as defined above.

The term “(arylcarbonyl)amino” as used herein, represents a group of theformula —NHC(═O)R^(m) wherein R^(m) is an aryl group, as defined above.Preferred (arylcarbonyl)amino is benzoylamino.

Usually, R¹ is hydrogen; C₁₋₁₀ alkyl unsubstituted or substituted byhalogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; hydroxy;C₃₋₆ cycloalkyl; halogen; ester; amido; nitro; cyano; amino; phenyl;alkylthio; alkylsulfonyl; alkylsulfinyl; heterocycle unsubstituted orsubstituted by alkyl groups; or guanidine. Preferably, R¹ is hydrogen;methyl; ethyl; i-propyl; n-propyl; cyclopropyl; n-butyl; i-butyl;t-butyl; 1-ethylpropyl; 2,4,4-trimethylpentyl; hydroxymethyl;chloromethyl; trifluoromethyl; 2,2,2-trifluoroethyl; cyanomethyl;2-(methylthio)ethyl; chloro; bromo; nitro; cyano; amino; aminocarbonyl;methoxycarbonyl; methylthio; methylsulfinyl; methylsulfonyl; phenyl;2-furyl; 3-furyl; 1H-pyrrol-2-yl; 1-methyl-1H-pyrrol-2-yl; 2-thienyl;1H-pyrazol-3-yl; 1,2,3-thiadiazol-4-yl or 1H-imidazol-2-yl. Morepreferably, R¹ is hydrogen; methyl; ethyl; i-propyl; n-propyl; n-butyl;methylthio; nitro; cyano; amino; chloro or 1H-pyrrol-2-yl. Mostpreferably, R¹ is hydrogen; methyl; methylthio; nitro; cyano; amino orchloro.

Usually, R² is hydrogen; C₁₋₄ alkyl unsubstituted or substituted byhydroxy, alkanoylamino or benzoylamino; halogen; ester; cyano; alkylcarbamate; [(N-methoxy-N-methyl)amino]carbonyl. Preferably, R² ishydrogen; methyl; hydroxymethyl; (acetylamino)methyl;(propionylamino)methyl; (benzoylamino)methyl;[(benzyloxy)carbonyl]amino; chloro or cyano. More preferably, R² ishydrogen; chloro or cyano.

Usually, R³ is hydrogen; C₁₋₄ alkyl unsubstituted or substituted byhydroxy; halogen; ester or cyano. Preferably, R³ is hydrogen;hydroxymethyl; chloro; cyano. More preferably, R³ is hydrogen or cyano.Most preferred R³ is hydrogen.

Usually, R⁴ is hydrogen; C₁₋₄ alkyl unsubstituted or substituted byhalogens; C₂₋₄ alkenyl substituted by halogens or phenyl groupunsubstituted or substituted by azido or/and halogens. Preferably, R⁴ ishydrogen; n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl;3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl;3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl;2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl;3-azido-2,4-difluorophenyl or 3-azido-2,4,6-trifluorophenyl. Morepreferably, R⁴ is hydrogen; n-propyl; 2,2-difluorovinyl; phenyl;3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl;3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl;2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl;3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. Most preferably, R⁴is n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl;3,5-difluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl;2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl or3-azido-2,4-difluorophenyl.

Usually, R^(4a) is hydrogen.

Usually, R⁵ is hydrogen.

Usually, R⁶ is hydrogen or C₁₋₁₀ alkyl unsubstituted or substituted byhydroxy or azido. Preferably, R⁶ is hydrogen or azidomethyl. Morepreferably R⁶ is hydrogen.

Usually R⁷ is hydrogen.

In other preferred embodiments, R⁶ and R⁷ are linked to form acyclopropyl.

In other preferred embodiments, R² and R³ can form together with theimidazole ring the following 1H-benzimidazole cycle

Usually, R⁸ is hydrogen.

Usually, R⁹ is hydrogen; halogen; C₁₋₃ alkyl or alkoxy. Preferably, R⁹is hydrogen; methyl; chloro or methoxy. More preferred R⁹ is hydrogen.

Usually, R¹⁰ is hydrogen; halogen; cyano; C₁₋₃ alkyl unsubstituted orsubstituted by halogens; or alkoxy. Preferably, R¹⁰ is methyl; hydrogen;trifluoromethyl; fluoro; cyano or methoxy. More preferred R¹⁰ ishydrogen; trifluoromethyl; fluoro or cyano.

Usually, R¹¹ is hydrogen.

In other preferred embodiments, R⁴, R^(4a) and R⁵ can form together withthe 2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-onecycle

Usually, R¹² is hydrogen or halogen. Preferably R¹² is hydrogen; chloroor fluoro. More preferred R¹² is hydrogen.

Usually, R¹³ is hydrogen; C₁₋₃ alkyl; halogen or thiazolyl unsubstitutedor substituted by alkyl groups, such as methylthiazolyl. Preferably R¹³is hydrogen; chloro; bromo or methyl. Most preferred R¹³ is chloro;bromo or methyl.

Usually R¹⁴ is hydrogen.

Usually, R¹⁵ is hydrogen.

Combinations of one or more of these preferred compound groups areespecially preferred.

Generally, among the embodiments, the compounds of formula I, orpharmaceutically acceptable salts thereof, are those wherein

R¹ is selected from hydrogen; C₁₋₁₀ alkyl unsubstituted or substitutedby halogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; C₃₋₆cycloalkyl; halogen; ester; amido; nitro; cyano; amino; phenyl;alkylthio; alkylsulfonyl; alkylsulfinyl; heterocycle unsubstituted orsubstituted by alkyl group; or guanidine;

R² is selected from hydrogen; C₁₋₄ alkyl unsubstituted or substituted byhydroxy, alkanoylamino or benzoylamino; halogen; ester; cyano; alkylcarbamate or [(N-methoxy-N-methyl)amino]carbonyl.

R³ is selected from hydrogen; C₁₋₄ alkyl unsubstituted or substituted byhydroxy; halogen; ester or cyano;

R⁴ is selected from hydrogen; C₁₋₄ alkyl unsubstituted or substituted byhalogens; C₂₋₄ alkenyl substituted by halogens or phenyl groupunsubstituted or substituted by azido or/and halogens;

R^(4a) is hydrogen;

R⁵ is hydrogen;

R⁶ is selected from hydrogen or C₁₋₁₀ alkyl unsubstituted or substitutedby hydroxy or azido;

R⁷ is hydrogen;

or R⁶ and R⁷ can be linked to form a cyclopropyl;

or R² and R³ can form together with the imidazole ring the following1H-benzimidazole cycle

R⁸ is hydrogen;

R⁹ is selected from hydrogen; halogen; C₁₋₃ alkyl; alkoxy;

R¹⁰ is selected from hydrogen; halogen; cyano or C₁₋₃ alkylunsubstituted or substituted by halogens; or alkoxy;

R¹¹ is hydrogen;

or R⁴, R^(4a) and R⁵ can form together with the 2-oxo-1-pyrrolidine ringthe following 1,3-dihydro-2H-indol-2-one cycle

R¹¹ is selected from hydrogen or halogen;

R¹¹ is selected from hydrogen; C₁₋₃ alkyl; halogen; thiazolylunsubstituted or substituted by alkyl groups, such as methylthiazolyl;

R¹⁴ is hydrogen;

R¹⁵ is hydrogen;

with the proviso that R⁴ is different from hydrogen when

represents a group of formula

In a preferred embodiment, the compounds of formula I, orpharmaceutically acceptable salt thereof, are those wherein

R¹ is selected from hydrogen; methyl; ethyl; i-propyl; n-propyl;cyclopropyl; n-butyl; i-butyl; t-butyl; 1-ethylpropyl;2,4,4-trimethylpentyl; trifluoromethyl; 2,2,2-trifluoroethyl;hydroxymethyl; chloromethyl; cyanomethyl; 2-(methylthio)ethyl; chloro;bromo; nitro; cyano; amino; aminocarbonyl; methoxycarbonyl; methylthio;methylsulfinyl; methylsulfonyl; phenyl; 2-furyl; 3-furyl;1H-pyrrol-2-yl; 1-methyl-1H-pyrrol-2-yl; 2-thienyl; 1H-pyrazol-3-yl;1,2,3-thiadiazol-4-yl; or 1H-imidazol-2-yl;

R² is selected from hydrogen; methyl; hydroxymethyl;(acetylamino)methyl; (propionylamino)methyl; (benzoylamino)methyl;(benzyloxycarbonyl)amino; chloro; or cyano;

R³ is selected from hydrogen; hydroxymethyl; chloro; cyano;

or R² and R³ can form together with the imidazole ring the following1H-benzimidazole cycle

R⁸ is hydrogen;

R⁹ is selected from hydrogen; methyl; choro; methoxy;

R¹⁰ is selected from methyl; hydrogen; trifluoromethyl; fluoro; cyano;or methoxy;

R¹¹ is hydrogen;

R⁴ is selected from hydrogen; n-propyl; 2,2-difluorovinyl; phenyl;3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl;3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl;2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl;3,4,5-trifluorophenyl; 3-azido-2,4-difluorophenyl; or3-azido-2,4,6-trifluorophenyl.

R^(4a) is hydrogen; R⁵ is hydrogen;

or R⁴, R^(4a) and R⁵ can form together with the 2-oxo-1-pyrrolidine ringthe following 1,3-dihydro-2H-indol-2-one cycle

R¹² is selected from hydrogen; chloro; fluoro;

R¹³ is selected from hydrogen; chloro; bromo; methyl;

R¹¹ is hydrogen;

R¹⁵ hydrogen;

R⁶ is selected from hydrogen; azidomethyl;

R⁷ is hydrogen;

or R⁶ and R⁷ are linked to form a cyclopropyl;

with the proviso that R⁴ is different from hydrogen when

represents a group of formula

In a more preferred embodiment, the compounds of formula I, orpharmaceutically acceptable salt thereof, are those wherein

R¹ is selected from hydrogen; methyl; ethyl; i-propyl; n-propyl;n-butyl; methylthio; nitro; cyano; amino; chloro; or 1H-pyrrol-2-yl;

R² is selected from hydrogen; chloro; cyano;

R³ is selected from hydrogen; cyano;

or R² and R³ can form together with the imidazole ring the following1H-benzimidazole cycle

R⁸ is hydrogen;

R⁹ is hydrogen;

R¹⁰ is selected from hydrogen; trifluoromethyl; fluoro; cyano;

R¹¹ is hydrogen;

R⁴ is selected from hydrogen; n-propyl; 2,2-difluorovinyl; phenyl;3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl;3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl;2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl;3,4,5-trifluorophenyl; or 3-azido-2,4-difluorophenyl;

R^(4a) is hydrogen;

R⁵ is hydrogen;

or R⁴, R^(4a) and R⁵ can form together with the 2-oxo-1-pyrrolidine ringthe following 1,3-dihydro-2H-indol-2-one cycle

wherein

R¹² is hydrogen;

R¹³ is selected from methyl; chloro; bromo;

R¹⁴ is hydrogen;

R¹⁵ hydrogen;

R⁶ is hydrogen;

R⁷ is hydrogen;

with the proviso that R⁴ is different from hydrogen when

represents a group of formula

In a most preferred embodiment, the compounds of formula I, orpharmaceutically acceptable salt thereof, are those wherein

R¹ is selected from hydrogen; methyl; methylthio; nitro; cyano; amino;chloro;

R² is selected from hydrogen; chloro; cyano;

R³ is hydrogen;

R⁴ is selected from n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl;3-fluorophenyl; 3,5-difluorophenyl; 2,3,4-trifluorophenyl;2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl;3-azido-2,4-difluorophenyl;

R^(4a) is hydrogen;

R⁵ is hydrogen;

or R⁴, R^(4a) and R⁵ can form together with the 2-oxo-1-pyrrolidine ringthe following 1,3-dihydro-2H-indol-2-one cycle

R¹² is hydrogen;

R¹³ is selected from chloro; bromo; methyl;

R¹¹ is hydrogen;

R¹⁵ hydrogen;

R⁶ is hydrogen;

R⁷ is hydrogen.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;4-(3-azido-2,4,6-trifluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(+4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-[(2-ethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl-1-[(2-propyl-1H-imidazol-1-yl)methyl]pyrrolidin-2-one;(+)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[2-(methylsulfinyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-tert-butyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1[1-(1H-imidazol-1-yl)cyclopropyl]pyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;1-{[2-(methylsulfonyl)-1H-imidazol-1-yl]methyl}-propylpyrrolidin-2-one;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxamide,4-(4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3-chloro-4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(4-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one;1-{[2-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;methyl1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxyla-te;1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile;1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2,4-dichloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(−)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(+)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(−)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(+)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)-1-pyrrolidinyl]methyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(+)-1-{[2-oxo-4-(2,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(2,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-[(5-methyl-2-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-ethyl-5-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2,5-dimethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[2-azido-1-(1H-imidazol-1-yl)ethyl]-4-propylpyrrolidin-2-one;1-[(4-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[(2-bromo-4,5-dichloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;(+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-{[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[4-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; benzyl1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-5-ylcarbamat-e;N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]acetamide;N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]benzamide;N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]propanamide;1-(1H-benzimidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl-1-[(2-propyl-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one;1-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;1-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-amino-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[2-(chloromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-on-e;{1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazol-2-yl}acetoni-trile;1-[(5-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one-;1-[(5-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5,6-dimethyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[2-isopropyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(6-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-propyl-1H-benzimidazole-5-car-bonitrile;1-{[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;1-[(5-fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[6-methyl-2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(6-methoxy-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;2-butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;1-{[2-[2-(methylthio)ethyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(5-fluoro-2-isobutyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[5-fluoro-2-(2,4,4-trimethylpentyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;2-cyclopropyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-(1H-pyrazol-3-yl)-1H-benzimidazole-5-carbonitrile;1-[(2-cyclopropyl-5-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[2-(3-furyl)-6-methoxy-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-cyclopropyl-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylp-yrrolidin-2-one;1-[(2-isopropyl-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-(1,2,3-thiadiazol-4-yl-)-1H-benzimidazole-5-carbonitrile;1-{[2-(1H-imidazol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[5-fluoro-2-(2,2,2-trifluoroethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[2-(1-ethylpropyl)-6-methoxy-1H-benzimidazol-1-yl]methyl}-4-propylpyrr-olidin-2-one;1-{[6-methoxy-2-(1-methyl-1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[2-(2-furyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propyl-pyrrolidin-2-one;4-propyl-1-{[2-thien-2-yl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl-}pyrrolidin-2-one;1-{[2-(3-furyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[2-cyclopropyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(1H-pyrrol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-methyl}pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;4-fluoro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;4-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one;1-[(2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile;and1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-c-arbonitrile.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one,1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-[(2-ethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl-1-[(2-propyl-1H-imidazol-1-yl)methyl]pyrrolidin-2-one;(+)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;4-(4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3-chloro-4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(4-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one;1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile;1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (+);1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[2-azido-1-(1H-imidazol-1-yl)ethyl]-4-propylpyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;(+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-propyl-1H-benzimidazole-5-car-bonitrile;1-{[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;1-[(5-fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;2-butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;1-[(5-fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one;1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbo-nitrile.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-on-e;4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one;1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile;1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;(+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;(+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one;1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbo-nitrile.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:(−)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one.

v) International Patent Application WO 2007/065595:

Compounds having formula I, their enantiomers, diastereoisomers andmixtures thereof (including all possible mixtures of stereoisomers), orpharmaceutically acceptable salts thereof,

wherein

R¹ is hydrogen or C₁₋₆ alkyl;

R² is hydrogen or C₁₋₄ alkyl;

R³ is a group of formula —CHR⁵R⁶ or a benzyl group;

R⁴ is C₁₋₈ alkyl optionally substituted by alkoxycarbonyl, C3-6cycloalkyl, aryl or heterocycle;

R⁵ is C2-4 alkyl;

R⁶ is C2-4 alkyl, amido or —COOR⁷;

R⁷ is C1-4 alkyl;

Usually when R³ is a benzyl group, then R⁴ is C₁₋₈ alkyl optionallysubstituted by alkoxycarbonyl.

Usually when R³ is a group of formula CHR⁵R⁶ then R⁴ is C₁₋₈ alkyloptionally substituted by C₃₋₆ cycloalkyl, aryl or heterocycle.

The term “alkyl”, as used herein, is a group which represents saturated,monovalent hydrocarbon radicals having straight (unbranched) or branchedmoieties, or combinations thereof, and containing 1-8 carbon atoms,preferably 1-6 carbon atoms; more preferably alkyl groups have 1-4carbon atoms. Alkyl moieties may optionally be substituted by 1 to 5substituents independently selected from the group consisting ofhydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl, acyl, aryl orheterocycle. Alkyl moieties may be optionally substituted by acycloalkyl as defined hereafter. Preferred alkyl groups are methyl,cyanomethyl, ethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl,2-oxopropyl, 3-hydroxypropyl, 2-propynyl, n-butyl, i-butyl, n-pentyl,3-pentyl, n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl,3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl,3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl, 2-phenylethyl,(3,5-dimethylisoxazol-4-yl)methyl or (5-nitro-2-furyl)methyl. Morepreferred alkyl groups are methyl, ethyl, cyanomethyl, 2-methoxyethyl,n-propyl, 3-hydroxypropyl, 2-propynyl, n-butyl, 3-pentyl, n-hexyl,benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl,(3,5-dimethylisoxazol-4-yl)methyl or (5-nitro-2-furyl)methyl. Mostpreferred alkyl groups are methyl, ethyl, 3-methoxybenzyl, 3-nitrobenzylor (5-nitro-2-furyl)methyl.

The term “cycloalkyl”, as used herein, represents a monovalent group of3 to 8, preferably 3 to 6 carbon atoms derived from a saturated cyclichydrocarbon, which may be substituted by any suitable group includingbut not limited to one or more moieties selected from groups asdescribed above for the alkyl groups. Preferred cycloalkyl group iscyclohexyl.

The term “aryl” as used herein, is defined as a phenyl group optionallysubstituted by 1 to 4 substituents independently selected from halogen,amino, nitro, alkoxy or aminosulfonyl. Preferred aryl groups are phenyl,2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-methoxyphenyl,3-nitrophenyl, 3-aminophenyl or 4-(aminosulfonyl)phenyl.

The term “phenyl”, as used herein, represents an aromatic hydrocarbongroup of formula C₆H₅.

The term “benzyl group”, as used herein, represents a group of formula—CH₂-aryl. Preferred benzyl groups are benzyl, 2-bromobenzyl,3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl,3-aminobenzyl or 4-(aminosulfonyl)benzyl. More preferred benzyl groupsare benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl or3-aminobenzyl. Most preferred alkyl groups are 3-methoxybenzyl or3-nitrobenzyl.

The term “halogen”, as used herein, represents an atom of fluorine,chlorine, bromine, or iodine. Preferred halogen is bromine.

The term “hydroxy”, as used herein, represents a group of formula —OH.

The term “cyano”, as used herein, represents a group of formula —CN.

The term “amino”, as used herein, represents a group of formula —NH₂.

The term “ethynyl”, as used herein, represents a group of formula —C≡CH.

The term “alkoxy”, as used herein, represents a group of formula —OR^(a)wherein R^(a) is an alkyl group, as defined above. Preferred alkoxygroup is methoxy.

The term “nitro”, as used herein, represents a group of formula —NO₂.

The term “amido”, as used herein, represents a group of formula—C(═O)NH2.

The term “acyl”, as used herein, represents a group of formula—C(═O)R^(b) wherein R^(b) is an alkyl group, as defined here above.Preferred acyl group is acetyl (—C(═O)Me).

The term “alkoxycarbonyl (or ester)”, as used herein, represents a groupof formula COOR^(c) wherein R^(c) is an alkyl group; with the provisothat R^(c) does not represent an alkyl alpha-substituted by hydroxy.Preferred alkoxycarbonyl group is ethoxycarbonyl.

The term “heterocycle”, as used herein, represents a 5-membered ringcontaining one or two heteroatoms selected from 0 or N. The heterocyclemay be substituted by one or two C₁₋₄ alkyl or nitro. Preferredheterocycles are (3, 5-dimethylisoxazol-4-yl) or (5-nitro-2-furyl). Mostpreferred heterocycle is (5-nitro-2-furyl).

Generally R¹ is hydrogen or C₁₋₆ alkyl. Usually R¹ is hydrogen or C₁₋₆alkyl optionally substituted by hydroxy, alkoxy, cyano, ethynyl,alkoxycarbonyl or acyl. Preferably R¹ is hydrogen, methyl, cyanomethyl,2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl,3-hydroxypropyl, 2-propynyl, n-pentyl or n-hexyl. More preferably R¹ ishydrogen, methyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropylor 2-propynyl. Most preferably R¹ is hydrogen.

Generally R² is hydrogen or C₁₋₄ alkyl. Usually R² is hydrogen orunsubstituted C₁₋₄ alkyl. Preferably R² is hydrogen, methyl or n-butyl.More preferably, R² is methyl.

Generally R³ is a group of formula CHR⁵R⁶ or a benzyl group. PreferablyR³ is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or3-bromobenzyl. Most preferably R³ is 1-(ethoxycarbonyl)propyl.

Generally R⁴ is C₁₋₈ alkyl optionally substituted by alkoxycarbonyl,C₃₋₆ cycloalkyl, aryl or heterocycle. Usually R⁴ is C₁₋₈ alkyloptionally substituted by cyclohexyl, phenyl, bromophenyl, aminophenyl,methoxyphenyl, nitrophenyl, aminosulfonylphenyl,3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl or ethoxycarbonyl. PreferablyR⁴ is n-butyl, i-butyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl,2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl,2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl,(5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl. More preferably R⁴is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl,(5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl. Most preferably R⁴is 3-methoxybenzyl, 3-nitrobenzyl or (5-nitro-2-furyl)methyl.

Generally R⁵ is C₂₋₄ alkyl. Usually R⁵ is unsubstituted C₂₋₄4 alkyl.Preferably R⁵ is ethyl.

Generally R⁶ is C₂₋₄ alkyl, amido or —COOR⁷. Usually R⁶ is unsubstitutedC₂₋₄ alkyl, amido or —COOR⁷. Preferably R⁶ is ethyl, amido orethoxycarbonyl. Most preferably R⁶ is ethoxycarbonyl.

Generally R⁷ is C₁₋₄ alkyl. Usually R⁷ is unsubstituted C₁₋₄ alkyl.Preferably, R⁷ is ethyl.

In some embodiments, the compounds are those having formula I, and theirenantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers), or pharmaceutically acceptablesalts thereof,

wherein

R¹ is hydrogen, C₁₋₆ alkyl optionally substituted by hydroxy, alkoxy,cyano, ethynyl, alkoxycarbonyl or acyl;

R² is hydrogen or unsubstituted C₁₋₄ alkyl;

R³ is a group of formula —CHR⁵ R⁶ or a benzyl group;

R⁴ is C₁₋₈ alkyl optionally substituted by cyclohexyl, phenyl,bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl,aminosulfonylphenyl, 3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl orethoxycarbonyl;

R⁵ is unsubstituted C₂₋₄ alkyl;

R⁶ is unsubstituted C₂₋₄ alkyl, amido or —COOR⁷;

R⁷ is unsubstituted C₁₋₄ alkyl;

with the proviso that when R¹ is hydrogen, R² is methyl, R³ is —CHR⁵ R⁶,

R⁶ is ethoxycarbonyl and R⁵ is ethyl, then R⁴ is different fromn-propyl, propyl, n-pentyl, n-heptyl, 3-bromobenzyl, 4-chlorobenzyl,4-methylbenzyl or 2-phenylethyl.

In the above embodiment, preferably, when R³ is a benzyl group, then R⁴is C₁₋₈ alkyl optionally substituted by alkoxycarbonyl.

In the above embodiment, preferably, when R³ is a group of formula—CHR⁵R⁶, then R⁴ is C₁₋₈ alkyl optionally substituted by C₃₋₆cycloalkyl, aryl or heterocycle.

In a preferred embodiment,

R¹ is hydrogen, methyl, cyanomethyl, 2-ethoxy-2-oxoethyl,2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl,n-pentyl or n-hexyl;

R² is hydrogen, methyl or n-butyl;

R³ is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or3-bromobenzyl;

R⁴ is n-butyl, i-butyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl,2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl,2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl,(5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl;

with the proviso that when R¹ is hydrogen, R² is methyl and R³ is1-(ethoxycarbonyl)propyl, then R⁴ is different from n-pentyl,3-bromobenzyl or 2-phenylethyl.

In the above embodiment, preferably, when R³ is 3-bromobenzyl, then R⁴is C₁₋₈ alkyl optionally substituted by alkoxycarbonyl.

In the above embodiment, preferably, when R³ is 3-pentyl,1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl, then R⁴ isdifferent from 1-(ethoxycarbonyl)propyl.

In a more preferred embodiment,

R¹ is hydrogen, methyl, cyanomethyl, 2-methoxyethyl, n-propyl,3-hydroxypropyl or 2-propynyl;

R² is methyl;

R³ is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or3-bromobenzyl;

R⁴ is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl,(5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl;

with the proviso that when R¹ is hydrogen, R² is methyl and R³ is1-(ethoxycarbonyl)propyl, then R⁴ is different from 3-bromobenzyl.

In the above embodiment, preferably, when R³ is 3-bromobenzyl, then R⁴is 1-(ethoxycarbonyl)propyl;

In the above embodiment, preferably, when R³ is 3-pentyl,1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl, then R⁴ isdifferent from 1-(ethoxycarbonyl)propyl;

In a most preferred embodiment, R¹ is hydrogen; R² is methyl; R³ is1-(ethoxycarbonyl)propyl; and R⁴ is 3-methoxybenzyl, 3-nitrobenzyl or(5-nitro-2-furyl)methyl.

A further embodiment consists in compounds wherein R² is methyl, R³ is agroup of formula —CHR⁵ R⁶ with R⁵ being C₂₋₄ alkyl, R⁶ being amido or—COOR⁷ and R⁷ being methyl or ethyl.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of: ethyl2-[(7-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(2-ethoxy-2-oxoethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl 2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl2-{[7-(3-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(2-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl 2-({7-[4-(aminosulfonyl)benzyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate; ethyl2-{[7-(4-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(cyclohexylmethyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[1,3-dimethyl-2,6-dioxo-7-(1-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[1,3-dimethyl-2,6-dioxo-7-(2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-[(1,7-dihexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-[(3-methyl-2,6-dioxo-1,7-dipentyl-2,3,6₁7-tetrahydro-1H-purin-8-yl)thio]butanoate;2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanamide;2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanamide;7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione;ethyl2-{8-[(3-bromobenzyl)thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}butanoate;and ethyl2-[(7-isobutyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of: ethyl2-[(7-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H purin-8-yl]thio}butanoate; ethyl2-{[7-(3-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl 2-{[7-(3-bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyi2-({3-methyi-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl 2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanamide;7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione;and ethyl2-{8-[(3-bromobenzyl)thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}butanoate.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of: ethyl2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;and ethyl2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate.

In some embodiments, the compounds are those having formula II, theirenantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers), or pharmaceutically acceptablesalts:

wherein R.sup.1 is hydrogen or C.sub.1-6 alkyl;

R.sup.2 is hydrogen or C.sub.1-4 alkyl;

R.sup.3 is a group of formula —CHR.sup.SR.sup.6 or a benzyl group;

R.sup.4 is C.sub.1-8 alkyl optionally substituted by alkoxycarbonyl,C.sub.3-6 cycloalkyl, aryl or heterocycle;

R.sup.5 is hydrogen or C.sub.1-4 alkyl;

R.sup.6 is C.sub.1-4 alkyl, amido or —COOR.sup.7;

R.sup.7 is C.sub.1-4 alkyl;

In the above embodiment, in some cases, when R.sup.3 is a benzyl group,then R.sup.4 is C.sub.1-8 alkyl optionally substituted byalkoxycarbonyl.

In the above embodiment, in some cases, when R.sup.3 is a group offormula —CHR.sup.5R.sup.6, then R.sup.4 is C.sub.1-8 alkyl optionallysubstituted by C.sub.3-6 cycloalkyl, aryl or heterocycle.

In some embodiments, the compounds are those compounds of formula II,their enantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers), or pharmaceutically acceptablesalts

wherein

R.sup.1 is hydrogen or C.sub.1-6 alkyl;

R.sup.2 is hydrogen or C.sub.1-4 alkyl;

R.sup.3 is a group of formula —CHR.sup.5R.sup.6 or a benzyl group;

R.sup.4 is C.sub.1-8 alkyl optionally substituted by alkoxycarbonyl,C.sub.3-6 cycloalkyl, aryl or heterocycle;

R.sup.5 is hydrogen or C.sub.1-4 alkyl;

R.sup.6 is C.sub.1-4 alkyl, amido or —COOR.sup.7;

R.sup.7 is C.sub.1-4 alkyl.

In some embodiments, the compounds are compounds of formula II selectedfrom ethyl2-[(7-heptyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]but-anoate;7-(3-bromobenzyl)-3-methyl-8-(propylthio)-3,7-dihydro-1H-purine-2,-6-dione;ethyl2-[(3-methyl-2,6-dioxo-7-pentyl-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]but-anoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl-]thio}butanoate;ethyl2-[(3-methyl-2,6-dioxo-7-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]but-anoate;7-(3-bromobenzyl)-8-[(3-chloro-2-hydroxypropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione;and ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl-]thio}propanoate.

In some embodiments, the compounds are compounds of formula I, theirenantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers), or pharmaceutically acceptablesalts

wherein

R.sup.1 is hydrogen or C.sub.1-6 alkyl;

R.sup.2 is hydrogen or C.sub.1-4 alkyl;

R.sup.3 is a group of formula —CHR.sup.5R.sup.6 or a benzyl group;

R.sup.4 is C.sub.1-8 alkyl optionally substituted by alkoxycarbonyl,C.sub.3-6 cycloalkyl, aryl or heterocycle;

R.sup.5 is C.sub.2-4 alkyl;

R.sup.6 is C.sub.2-4 alkyl, amido or —COOR.sup.7;

R.sup.7 is C.sub.1-4 alkyl;

In another embodiment, the compounds are compounds having formula II,their enantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers), or pharmaceutically acceptablesalts thereof,

wherein

R.sup.1 is hydrogen or C.sub.1-6 alkyl;

R.sup.2 is hydrogen or C.sub.1-4 alkyl;

R.sup.3 is a group of formula —CHR.sup.5R.sup.6 or a benzyl group;

R.sup.4 is C.sub.1-8 alkyl optionally substituted by alkoxycarbonyl,C.sub.3-6 cycloalkyl, aryl or heterocycle;

R.sup.5 is hydrogen or C.sub.1-4 alkyl;

R.sup.6 is C.sub.1-4 alkyl, amido or —COOR.sup.7;

R.sup.7 is C.sub.1-4 alkyl;

vi) International Patent Application Publication No. WO2010/144712

In one embodiment, a chemical composition that includes a LEV derivativeof Formula 1 or Formula 2 is disclosed.

n of Formula 2 and L, X, and Y of Formulas 1 and 2 are defined asfollows: a) n is an integer with a value of 0 to 8; b) L is one of thegroup consisting of CH2, CO, NHCO, NHCOO, CONH, NH, O, or S, andcombinations thereof; c) X is an end group, an aromatic group, an arylgroup, or a saturated, unsaturated, substituted, unsubstituted, straightchain, or branched chain aliphatic group having from 1 to 10 carbonand/or hetero chain atoms, the hetero chain atoms being selected fromthe group consisting of oxygen, nitrogen, sulfur, or phosphorus, andcombinations thereof; and d) Y is optional and if present is one of afunctional group selected from group consisting of alcohol amine, amide,carboxylic acid, aldehyde, ester, iminoester, isocyanate,isothiocyanate, anhydride, thiol, thiolacetone, diazonium, NHS, CO—NHS,O—NHS, maleimido; or e) Y is a Yi-Z where Yi is selected from the groupconsisting of COO, CO, O, CONH, NHCO, or NH and Z is an operative group.

In one embodiment of the method, the operative group of Z is selectedfrom the group consisting of detectable labels, antigenic carriers,coupling agents, end groups, proteins, lipoproteins, glycoproteins,polypeptides, polysaccharides, nucleic acids, polynucleotides, teichoicacids, radioactive isotopes, enzymes, enzyme fragments, enzyme donorfragments, enzyme acceptor fragments, enzyme substrates, enzymeinhibitors, coenzymes, fluorescent moieties, phosphorescent moieties,anti-stokes up-regulating moieties, chemiluminescent moieties,luminescent moieties, dyes, sensitizers, particles, microparticles,magnetic particles, solid supports, liposomes, ligands, receptors,hapten radioactive isotopes, and combinations thereof.

vii) International Patent Application Publication No. WO2010/002869

The present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: each Z isindependently selected from hydrogen and deuterium; R1 is an n-propylgroup having zero to seven deuterium atoms; R2 is an ethyl group havingzero to five deuterium atoms, and when each R has zero deuterium atoms,at least one Z is deuterium. One embodiment of this invention providescompounds of Formula I wherein R1 is selected from CD3CH2CH2-,CD3CD2CH2-, CD3CH2CD2-, CH3CH2CD2-, CH3CD2CD2-, CD3CD2CD2- orCH3CH2CH2-. In a more specific embodiment, R1 is CD3CD2CD2- orCD3CD2CH2-. In one aspect of these embodiments, Z1 and Z2 are bothhydrogen.

In another aspect of these embodiments, Z1 and Z2 are both deuterium.

In another embodiment, R2 is selected from CH3CH2-, CD3CH2-, CH3CD2-, orCD3CD2-. In a more specific embodiment, R2 is selected from CH3CH2- orCD3CD2-. In one aspect of these embodiments, Z1 and Z2 are bothhydrogen. In another aspect of these embodiments, Z1 and Z2 are bothdeuterium.

The R and Z variables as described above may be selected and takentogether to provide more specific embodiments of this invention. Forexample, in one embodiment, R1 is CD3CH2CH2-, CD3CD2CH2-, CD3CH2CD2-,CH3CH2CD2-, CH3CD2CD2-, CD3CD2CD2- or CH3CH2CH2-; and R2 is selectedfrom CH3CH2-, CD3CH2-, CH3CD2-, or CD3CD2-. In one aspect of thisembodiment, R2 is CH3CH2- or CD3CD2-. [0039] In another embodiment, R1is CD3CD2CD2- or CD3CD2CH2-; and R2 is selected from CH3CH2-, CD3CH2-,CH3CD2-, or CD3CD2-. In one aspect of this embodiment, R2 is CH3CH2- orCD3 CD2-.

Examples of specific compounds of this invention include the following:

viii) 20090312333

The compounds of the present invention are those covered by formula (I),their diastereomers and mixtures, or a pharmaceutically acceptable saltthereof

R1 is hydrogen, substituted or unsubstituted C1-12 alkyl, substituted orunsubstituted aryl or substituted or unsubstituted 3-8 memberedheterocycle.

R2 is hydrogen. Alternatively, R1 and R2 may be linked together in sucha way to form a C3-6 cycloalkyl.

R3 is either

(a) a substituted or unsubstituted heterocycle linked to the rest of themolecule via one of its C atoms, said heterocycle is selected from thegroup consisting of:

-   1H-benzimidazol-6-yl;-   1H-benzimidazol-7-yl;-   imidazo[1,2-a]pyridin-3-yl;-   imidazo[1,2-a]pyrimidin-3-yl;-   imidazo[1,2-b][1,2,4]triazin-7-yl;-   imidazo[1,2-b]pyridazin-3-yl;-   5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   1H-indol-2-yl;-   1H-indol-3-yl;-   1H-indol-4-yl;-   1H-indol-7-yl;-   isoxazol-4-yl;-   1H-pyrazol-4-yl;-   1H-pyrazol-5-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   1H-pyrazolo[3,4-b]pyridin-3-yl;-   pyridazin-4-yl;-   pyridin-2-yl;-   pyridin-3-yl;-   pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-5-yl;-   1H-pyrrolo[2,3-c]pyridin-2-yl;-   1H-pyrrolo[2,3-c]pyridin-3-yl;-   1H-pyrrolo[3,2-b]pyridin-3-yl;-   1H-pyrrolo[3,2-c]pyridin-2-yl;-   1H-pyrrolo[3,2-c]pyridin-3-yl;-   1,3,4-thiadiazol-2-yl;-   1,3-thiazol-5-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-7-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-8-yl;-   indolizin-3-yl;-   or R3 is-   (b) a substituted or unsubstituted heterocycle linked to the rest of    the molecule via-   one of its N atoms, said heterocycle is selected from the group    consisting of:-   1H-1,2,3-benzotriazol-1-yl;-   1H-imidazo[4,5-b]pyridin-1-yl;-   3H-imidazo[4,5-b]pyridin-3-yl;-   7H-imidazo[4,5-c]pyridazin-7-yl;-   1H-indol-1-yl;-   2,3-dihydro-1H-indol-1-yl;-   9H-purin-9-yl;-   1H-pyrazolo[3,4-b]pyridin-1-yl;-   2H-pyrazolo[3,4-b]pyridin-2-yl;-   1H-pyrrolo[2,3-b]pyridin-1-yl;-   1H-pyrrolo[3,2-b]pyridin-1-yl;-   3,4-dihydroquinolin-1(2H)-yl;-   8H-isothiazolo[5,4-b]indol-8-yl;-   1H-1,2,4-triazol-1-yl;-   1H-pyrrol-1-yl;-   2-chloro-1H-benzimidazol-1-yl.

R4 in formula (I) is selected from the group comprising or consisting ofhydrogen; C1-12 alkyl optionally substituted by halogen, C1-4 alkoxy,C1-4 alkylthio, azido, nitrooxy or an aryl; C2-12 alkenyl optionallysubstituted by halogen; C2-12 alkynyl optionally substituted by halogen;azido; alkoxycarbonylamino; arylsulfonyloxy; a substituted orunsubstituted aryl; or a 3-8 membered substituted or unsubstitutedheterocycle;

In a specific embodiment R4 is hydrogen; or R4 is C1-12 alkyl or a C1-6alkyl, optionally substituted by halogen, C1-4 alkoxy, C1-4 alkylthio,azido or nitrooxy; or R4 is C2-12 alkenyl or a C1-6 alkenyl optionallysubstituted by halogen; or R4 is C2-12 alkynyl or a C1-6 alkynyloptionally substituted by halogen; or R4 is alkoxycarbonylamino.

R5 is hydrogen;

Alternatively R4 may form together with R5 and the 2-oxo-1-pyrrolidinering a 1,3-dihydro-2H-indol-2-one ring of the following structure:

The asterisk * indicates the point of attachment of the substituents;

R6 is hydrogen or halogen.

R7 in formula (I) is selected from the group comprising or consisting ofhydrogen; nitro; halogen; heterocycle; amino; aryl; C1-12 alkyloptionally substituted by at least one halogen; or C1-12 alkoxyoptionally substituted by at least one halogen.

R8 in formula (I) is selected from the group comprising or consisting ofhydrogen,

C1-12 alkyl optionally substituted by halogen, or halogen.

R9 in formula (I) is selected from the group comprising or consisting ofhydrogen,

C1-12 alkyl optionally substituted by halogen, or halogen.

A further aspect of the present invention consists in compounds offormula (I)

wherein

R1 and R2 are both hydrogen.

R3 is:

(a) a substituted or unsubstituted heterocycle linked to the rest of themolecule via one of its C atoms selected from the group consisting of:

-   1H-benzimidazol-6-yl;-   1H-benzimidazol-7-yl;-   imidazo[1,2-a]pyridin-3-yl;-   imidazo[1,2-a]pyrimidin-3-yl;-   imidazo[1,2-b][1,2,4]triazin-7-yl;-   imidazo[1,2-b]pyridazin-3-yl;-   5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   1H-indol-2-yl;-   1H-indol-3-yl;-   1H-indol-4-yl;-   1H-indol-7-yl;-   isoxazol-4-yl;-   1H-pyrazol-4-yl;-   1H-pyrazol-5-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   1H-pyrazolo[3,4-b]pyridin-3-yl;-   pyridazin-4-yl;-   pyridin-2-yl;-   pyridin-3-yl;-   pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-5-yl;-   1H-pyrrolo[2,3-c]pyridin-2-yl;-   1H-pyrrolo[2,3-c]pyridin-3-yl;-   1H-pyrrolo[3,2-b]pyridin-3-yl;-   1H-pyrrolo[3,2-c]pyridin-2-yl;-   1H-pyrrolo[3,2-c]pyridin-3-yl;-   1,3,4-thiadiazol-2-yl;-   1,3-thiazol-5-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-7-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-8-yl;-   indolizin-3-yl.

Alternatively R3 is:

(b) a substituted or unsubstituted heterocycle linked to the rest of themolecule via one of its N atoms selected from the group consisting of:

-   1H-1,2,3-benzotriazol-1-yl;-   1H-imidazo[4,5-b]pyridin-1-yl;-   3H-imidazo[4,5-b]pyridin-3-yl;-   7H-imidazo[4,5-c]pyridazin-7-yl;-   1H-indol-1-yl;-   2,3-dihydro-1H-indol-1-yl;-   9H-purin-9-yl;-   1H-pyrazolo[3,4-b]pyridin-1-yl;-   2H-pyrazolo[3,4-b]pyridin-2-yl;-   1H-pyrrolo[2,3-b]pyridin-1-yl;-   1H-pyrrolo[3,2-b]pyridin-1-yl;-   3,4-dihydroquinolin-1(2H)-yl;-   8H-isothiazolo[5,4-b]indol-8-yl;-   1H-1,2,4-triazol-1-yl;-   1H-pyrrol-1-yl;-   2-chloro-1H-benzimidazol-1-yl.

R4 in formula (I) is selected from the group comprising or consisting ofhydrogen; C1-12 alkyl optionally substituted by halogen or C1-4 alkoxy;C2-12 alkenyl optionally substituted by halogen; C2-12 alkynyloptionally substituted by halogen.

In a further specific embodiment R4 is n-propyl, 2,2,2-trifluoroethyl,2-chloro-2,2-difluoroethyl, 2 bromo-2,2-difluoroethyl,2,2-difluorovinyl.

In another specific embodiment R4 is phenyl, 2,3,5-trifluorophenyl or3-chloro-4-fluorophenyl.

R5 is hydrogen;

A further embodiment of the present invention consists in compounds offormula (I) wherein R4 forms together with R5a1,3-dihydro-2H-indol-2-one ring

The asterisk * indicates the point of attachment of the heteroarylalkylene substituent, and wherein

R6 is hydrogen;

R7 is chlorine;

R8 is hydrogen;

R9 is hydrogen.

A further embodiment of the present invention consists in compounds offormula (I) wherein R3 is a substituted or unsubstituted heterocyclelinked to the rest of the molecule via one of its C atoms and isselected from the group consisting of:

-   imidazo[1,2-a]pyrimidin-3-yl;-   imidazo[1,2-b][1,2,4]triazin-7-yl;-   imidazo[1,2-b]pyridazin-3-yl;-   5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   isoxazol-4-yl;-   1H-pyrazol-4-yl;-   1H-pyrazol-5-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   1H-pyrazolo[3,4-b]pyridin-3-yl;-   pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-5-yl;-   1H-pyrrolo[2,3-c]pyridin-2-yl;-   1H-pyrrolo[2,3-c]pyridin-3-yl;-   1,3-thiazol-5-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-8-yl;-   indolizin-3-yl.

In a further specific embodiment R3 is a heterocycle linked to the restof the molecule via one of its C atoms and is selected from the groupconsisting of:

-   imidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   1H-pyrazol-4-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1,3-thiazol-5-yl;

Said heterocycles are optionally substituted by e.g. a methyl, n-propyl,trifluoromethyl, cyclopropyl, bromine, chlorine, fluorine, iodine,methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy,cyclopropylmethoxy, cyclobutylmethoxy, amino, methylamino,cyclopropylamino, cyclobutylamino, 1-pyrrolidinyl, cyano, phenyl, benzylor 3-thienyl.

In a further specific embodiment R3 is a heterocycle linked to the restof the molecule via one of its C atoms and is selected from the groupconsisting of: 6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl,6-(cyclopropyloxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl,6-propoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl,6-chloroimidazo[2,1-b][1,3]thiazol-5-yl,2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl, 5-chloro-1H-imidazol-4-yl,5-bromo-1H-imidazol-4-yl, 4-bromo-1H-imidazol-5-yl,4-chloro-1H-imidazol-5-yl, 1H-imidazol-5-yl, 1-methyl-1H-imidazol-5-yl,4-chloro-1-methyl-1H-imidazol-5-yl, 1H-pyrazol-4-yl,1H-pyrrolo[2,3-b]pyridin-3-yl.

A further embodiment of the present invention consists in compounds offormula (I) wherein R3 is a heterocycle linked to the rest of themolecule via one of its C atoms and is a substituted or unsubstitutedimidazo[1,2-a]pyridin-3-yl.

Said imidazo[1,2-a]pyridin-3-yl is optionally substituted by e.g. amethyl, cyclopropyl, bromine, chlorine, fluorine, iodine.

In a further specific embodiment R3 is a heterocycle linked to the restof the molecule via one of its C atoms and is selected from the groupconsisting of: imidazo[1,2-a]pyridin-3-yl,6-methylimidazo[1,2-a]pyridin-3-yl, 2-chloroimidazo[1,2-a]pyridin-3-yl.

A further embodiment of the present invention consists in compounds offormula (I) wherein R3 is a substituted or unsubstituted heterocyclelinked to the rest of the molecule via one of its N atoms and isselected from the group consisting of:

-   3H-imidazo[4,5-b]pyridin-3-yl;-   1H-indol-1-yl;-   1H-pyrrolo[2,3-b]pyridin-1-yl;-   1H-pyrrolo[3,2-b]pyridin-1-yl;-   1H-pyrrol-1-yl;-   2-chloro-1H-benzimidazol-1-yl.

A specific further embodiment of the present invention consists incompounds of formula (I) wherein R3 is a heterocycle linked to the restof the molecule via one of its N atoms and is selected from the groupconsisting of:

-   3H-imidazo[4,5-b]pyridin-3-yl;-   1H-pyrrolo[3,2-b]pyridin-1-yl;-   1H-pyrrol-1-yl;-   2-chloro-1H-benzimidazol-1-yl;

Said heterocycles may optionally be substituted by trifluoromethyl,cyclopropyl, bromine, chlorine, fluorine, methoxy or cyano.

In a further specific embodiment R3 is a heterocycle linked to the restof the molecule via one of its C atoms and is selected from the groupconsisting of 6-bromo-2-chloro-3H-imidazo[4,5-b]pyridin-3-yl,6-bromo-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl,1H-pyrrolo[3,2-b]pyridin-1-yl, 2,5-dichloro-1H-pyrrol-1-yl,2-chloro-5-methoxy-1H-benzimidazol-1-yl,5-bromo-2-chloro-1H-benzimidazol-1-yl or2,5-dichloro-1H-benzimidazol-1-yl.

A further embodiment of the present invention consists in compounds offormula (I) wherein R1, R2 and R5 are hydrogen.

R4 is a C1-6 alkyl optionally substituted by halogen, a C2-6 alkenyloptionally substituted by halogen or C2-12 alkynyl optionallysubstituted by halogen.

-   R3 is selected from the group consisting of;-   imidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   1H-pyrazol-4-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1,3-thiazol-5-yl;

and optionally substituted by methyl, n-propyl, trifluoromethyl,cyclopropyl, bromine, chlorine, fluorine, iodine, methoxy, ethoxy,propoxy, isopropoxy, cyclopropyloxy, cyclopropylmethoxy,cyclobutylmethoxy, amino, methylamino, cyclopropylamino,cyclobutylamino, 1-pyrrolidinyl, cyano, phenyl, benzyl or 3-thienyl.

A further embodiment of the present invention consists in compounds offormula (I) wherein R1, R2 and R5 are hydrogen.

R4 is a C1-6 alkyl optionally substituted by halogen, a C2-6 alkenyloptionally substituted by halogen or C2-12 alkynyl optionallysubstituted by halogen.

R3 is selected from the group consisting of

-   3H-imidazo[4,5-b]pyridin-3-yl;-   1H pyrrolo[3,2-b]pyridin-1-yl;-   1H-pyrrol-1-yl;-   2-chloro-1H-benzimidazol-1-yl;

optionally substituted by trifluoromethyl, cyclopropyl, bromine,chlorine, fluorine, methoxy or cyano.

A further embodiment of the invention consists in compounds of formula(I), their diastereomers and mixtures, or a pharmaceutically acceptablesalt thereof

R1, R2 and R5 are hydrogen.

R3 is a substituted or unsubstituted heterocycle linked to the rest ofthe molecule via one of its C atoms, said heterocycle is selected fromthe group consisting of:

-   1H-benzimidazol-6-yl;-   1H-benzimidazol-7-yl;-   imidazo[1,2-a]pyridin-3-yl;-   imidazo[1,2-a]pyrimidin-3-yl;-   imidazo[1,2-b][1,2,4]triazin-7-yl;-   imidazo[1,2-b]pyridazin-3-yl;-   5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   1H-indol-2-yl;-   1H-indol-3-yl;-   1H-indol-4-yl;-   1H-indol-7-yl;-   isoxazol-4-yl;-   1H-pyrazol-4-yl;-   1H-pyrazol-5-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   1H-pyrazolo[3,4-b]pyridin-3-yl;-   pyridazin-4-yl;-   pyridin-2-yl;-   pyridin-3-yl;-   pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-5-yl;-   1H-pyrrolo[2,3-c]pyridin-2-yl;-   1H-pyrrolo[2,3-c]pyridin-3-yl;-   1H-pyrrolo[3,2-b]pyridin-3-yl;-   1H-pyrrolo[3,2-c]pyridin-2-yl;-   1H-pyrrolo[3,2-c]pyridin-3-yl;-   1,3,4-thiadiazol-2-yl;-   1,3-thiazol-5-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-7-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-8-yl;-   indolizin-3-yl;

Particularly preferred are imidazo[1,2-a]pyridin-3-yl;imidazo[1,2-a]pyrimidin-3-yl; imidazo[1,2-b]pyridazin-3-yl;1H-imidazol-4-yl; 1H-imidazol-5-yl;

R4 is a substituted or unsubstituted phenyl moiety;

A further embodiment of the present invention consists in compounds offormula (I) wherein R1 is hydrogen or C1-12 alkyl;

R2 is hydrogen;

R3 is an aromatic 5-membered heterocycle linked to the rest of themolecule via one of its C atoms;

R4 is hydrogen, C1-12 alkyl or aryl;

R5 is hydrogen;

Alternatively, R4 can form together with R5 and the 2-oxo-1-pyrrolidinering the following 1,3-dihydro-2H-indol-2-one cycle

wherein the asterisk * indicates the point of attachment of thesubstituents;

R6 is hydrogen or halogen;

In this embodiment R4 may not be hydrogen when R3 is substituted1H-pyrazol-5-yl. Also this embodiment does not comprise5-(2′-oxo-1′-pyrrolidinyl)methyl-1,3,4-tricarbomethoxy-pyrazole which isdisclosed in A. Padwa et al J. Org. Chem. 2000, 65, 5223-5232 withoutany biological activity though.

In this embodiment wherein R3 is an aromatic 5-membered heterocyclelinked to the rest of the molecule via one of its C atoms, specificmoieties R3 may be selected from 1,3-thiazol-5-yl, 1H-imidazol-4-yl,1H-imidazol-5-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl,2-oxo-2,3-dihydro-1,3-thiazol-5-yl, each of them being optionallysubstituted by 1 to 3 substituents independently selected from methyl,chlorine, bromine, amino, methylamino, dimethylamino,(2-oxo-4-propylpyrrolidin-1-yl)methyl, 1-pyrrolidinyl, amido, cyano,methoxy, phenyl, 4-methylphenyl-sulfonyl, benzyl or2-(benzylamino)-2-oxoethyl.

In this embodiment, more specific moieties R3 are selected from2-(methylamino)-1,3-thiazol-5-yl; 2-pyrrolidin-1-yl-1,3-thiazol-5-yl;5-bromo-1H-imidazol-4-yl; 5-chloro-1H-imidazol-4-yl; 1H-imidazol-5-yl;1-methyl-1H-imidazol-5-yl; 4-bromo-1-methyl-1H-imidazol-5-yl;4-chloro-1H-imidazol-5-yl; 4-chloro-1-methyl-1H-imidazol-5-yl;4-cyano-1-methyl-1H-imidazol-5-yl; 1H-pyrazol-4-yl;3,5-dimethyl-1H-pyrazol-4-yl; 3-methyl-1H-pyrazol-4-yl.

In this embodiment, most specific moieties R3 are selected from5-bromo-1H-imidazol-4-yl; 5-chloro-1H-imidazol-4-yl; 1H-imidazol-5-yl;4-bromo-1-methyl-1H-imidazol-5-yl; 4-chloro-1-methyl-1H-imidazol-5-yl;1H-pyrazol-4-yl.

Still in this embodiment, a specific moiety R1 is selected from hydrogenor ethyl.

Still in this embodiment, a specific moiety R4 is selected fromhydrogen, n-propyl, 2,3,5-trifluorophenyl or phenyl.

A further embodiment of the present invention consists in compoundshaving the specific formula (Ia).

In formula (Ia) the substituent R10 is hydrogen; halogen; C1-4 alkyloptionally substituted by at least one halogen; C1-4 alkoxy;methoxycarbonyl; nitro; amino; alkylamino; amido; or alkanoyl-amino.Preferably R10 is hydrogen.

R11 is hydrogen; halogen; C1-4 alkyl optionally substituted by at leastone halogen; C1-4 alkoxy; methoxycarbonyl; nitro; amino; alkylamino;amido; or alkanoylamino. Preferably R11 is hydrogen.

R4 is C1-4 alkyl optionally substituted by at least one halogen; or C2-4alkenyl optionally substituted by at least one halogen. Preferably R4 isn-propyl.

Still in this aspect of the invention a specific embodiment relates toan embodiment wherein R10 is selected from hydrogen; methyl; fluorine;chlorine; bromine; methoxy; methoxycarbonyl; nitro; or trifluoromethyl,while R11 is selected from hydrogen; methyl; fluorine; chlorine;bromine; methoxy; methoxycarbonyl; nitro; or trifluoromethyl; and R3 isn-propyl.

Specific compounds of the present invention are those selected from thegroup consisting of:

-   1-[(1-methyl-1H-benzimidazol-6-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(1H-benzimidazol-7-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(5-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-phenylpyrrolidin-2-one;-   1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpyrrolidin-2-one;-   1-[(6-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(8-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-iodoimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(7-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6,8-dibromoimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6,8-dichloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-chloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-chloro-2-cyclopropylimidazo[1,2-a]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-(imidazo[1,2-a]pyrimidin-3-ylmethyl)-4-propylpyrrolidin-2-one;-   1-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-4-propyl    pyrrolidin-2-one;-   1-(imidazo[1,2-a]pyrimidin-3-ylmethyl)-4-phenylpyrrolidin-2-one;-   1-[(6-chloroimidazo[1,2-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(6-phenylimidazo[1,2-b][1,2,4]triazin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl]-4-phenylpyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-phenylpyrrolidin-2-one;-   5-chloro-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-1,3-dihydro-2H-indol-2-one;-   1-{[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-isopropoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(benzyloxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-cyclopropyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(dimethylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2-chloro-2,2-difluoroethyl)-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[6-(methylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-hydroxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(methylthio)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   4-(2-bromo-2,2-difluoroethyl)-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[6-(methylsulfonyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(methylsulfinyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one;-   1-[(6-chloro-2-cyclobutylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-amino-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(ethylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   4-propyl-1-{[6-(propylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2-bromo-2,2-difluoroethyl)-1-{[6-(propylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-(propylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-methoxy-2-(4-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-propyl-1-{[6-pyrrolidin-1-yl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2-bromo-2,2-difluoroethyl)-1-{[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[6-(cyclopropylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-(isopropylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[2-cyclopropyl-6-(propylamino)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{(2-cyclopropyl-6-[(2-fluoroethyl)amino]imidazo[1,2-b]pyridazin-3-yl}methyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{(2-cyclopropyl-6-[(2,2-difluoroethyl)amino]imidazo[1,2-b]pyridazin-3-yl}methyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{(2-cyclopropyl-6-[(2,2,2-trifluoroethyl)amino]imidazo[1,2-b]pyridazin-3-yl}methyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   4-(2,2-difluoroethyl)-1-{[2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[2-cyclopropyl-6-(cyclopropylamino)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-chloro-2-cyclobutylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(3-chloro-4-fluorophenyl)pyrrolidin-2-one;-   1-{[6-(butylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-(cyclobutylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(2-cyclopropyl-6-methoxy    imidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-ethoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-isopropoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[6-(cyclopropylmethoxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-(cyclobutylmethoxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-(cyclopropyloxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-propoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   3-{[4-(2,2-difluorovinyl)-2-oxopyrrolidin-1-yl]methyl}-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-6-carbonitrile;-   4-(2,2-difluorovinyl)-1-{[6-thien-3-yl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-phenyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-methyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-pyridin-3-yl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-propyl-1-{[2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-[(6-methylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(2-cyclopropyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-methylimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(3H-imidazo[4,5-b]pyridin-7-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(3H-imidazo[4,5-b]pyridin-7-ylmethyl)-4-phenylpyrrolidin-2-one;-   4-phenyl-1-[(5-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]pyrrolidin-2-one;-   4-phenyl-1-{[5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}pyrrolidin-2-one;-   1-[(6-bromo-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-{[5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}pyrrolidin-2-one;-   1-[(6-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[1-(1H-imidazol-4-yl)propyl]pyrrolidin-2-one;-   1-[(5-methyl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one;-   1-[(2-methyl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one;-   1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-one;-   1-({1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-4-yl}methyl)-4-propylpyrrolidin-2-one;-   1-[(5-chloro-1H-imidazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(5-bromo-1H-imidazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(5-bromo-1H-imidazol-4-yl)methyl]-5-chloro-1,3-dihydro-2H-indol-2-one;-   1-(1H-imidazol-5-ylmethyl)pyrrolidin-2-one;-   1-[(1-methyl-1H-imidazol-5-yl)methyl]pyrrolidin-2-one;-   1-methyl-5-[(2-oxopyrrolidin-1-yl)methyl]-1H-imidazole-4-carbonitrile;-   1-(1H-imidazol-5-ylmethyl)-4-phenylpyrrolidin-2-one;-   1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-phenylpyrrolidin-2-one;-   1-[(4-methoxy-1-methyl-1H-imidazol-5-yl)methyl]pyrrolidin-2-one;-   1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-4-carbonitrile;-   1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-4-carboxamide;-   N-benzyl-2-{5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetamide;-   1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carbonitrile;-   1-[(4-chloro-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-methyl-5-[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl-1H-imidazole-4-carbonitrile;-   1-[(4-bromo-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2,4-dichloro-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;    benzyl    1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-2-ylcarbamate;-   1-[(4-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   5-chloro-1-(1H-imidazol-5-ylmethyl)-1,3-dihydro-2H-indol-2-one;-   1-[(2,4-dichloro-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(2,4-dichloro-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(2-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(4-bromo-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   5-chloro-1-[(1-methyl-1H-imidazol-5-yl)methyl]-1,3-dihydro-2H-indol-2-one;-   1-[(4-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-(1H-indol-2-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(1H-indol-3-ylmethyl)-4-propylpyrrolidin-2-one;-   3-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-indole-5-carbonitrile;-   1-[(2-methyl-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(7-methoxy-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-nitro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-{[6-(trifluoromethyl)-1H-indol-3-yl]methyl}pyrrolidin-2-one;-   1-[(5-nitro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(7-fluoro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-chloro-2-methyl-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[1H-indol-3-yl(phenyl)methyl]-4-propylpyrrolidin-2-one;-   1-[1-(1H-indol-3-yl)propyl]-4-propylpyrrolidin-2-one;-   1-[2-furyl(1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   3-[(2-oxo-4-propylpyrrolidin-1-yl)(phenyl)methyl]-1H-indole-5-carbonitrile;-   1-(1H-indol-4-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(1H-indol-7-ylmethyl)-4-propyl pyrrolidin-2-one;-   1-(isoxazol-4-ylmethyl)-4-propylpyrrolidin-2-one;-   1-[(1-phenyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(1-benzyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   4-(2,3,5-trifluorophenyl)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]pyrrolidin-2-one;-   4-phenyl-1-(1H-pyrazol-4-ylmethyl)pyrrolidin-2-one;-   1-({1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-(1H-pyrazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(1-chloro-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(3-methyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(5-amino-1,3-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(5-amino-1-methyl-1H-pyrazol-4-yl)methyl]-4-propylpyrrolidin-2-one;-   (−)-1-(1H-pyrazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   (+)-1-(1H-pyrazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-(1H-pyrazol-4-ylmethyl)-1,3-dihydro-2H-indol-2-one;-   5-chloro-1-(1H-pyrazol-4-ylmethyl)-1,3-dihydro-2H-indol-2-one;-   5-chloro-1-({1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-1,3-dihydro-2H-indol-2-one;-   1-{[5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(5-amino-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(1-benzyl-5-chloro-1H-pyrazol-4-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-(1H-pyrazol-5-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(4-bromo-1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(6-bromo-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-[(2-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   1-[(6-bromo-2-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-tert-butylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-tert-butyl-6-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[2-(2-furyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(2-methyl-6-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-methyl-6-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[2-methyl-6-(1H-pyrrol-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-({6-[(1E)-hex-1-enyl]-2-methylpyrazolo[1,5-a]pyrimidin-3-yl}methyl)-4-propylpyrrolidin-2-one;-   1-[(6-chloro-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[2-methyl-6-(phenylethynyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-hydroxy-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   1-[(6-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-chloropyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(5,6-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   1-[(5-methoxy    pyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[2-(4-bromophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(2-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   1-{[2-(4-chlorophenyl)-6-methylpyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-chloro-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-chloro-2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(2-cyclopropyl-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(5-chloro-2,6-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   4-propyl-1-(pyridin-3-ylmethyl)pyrrolidin-2-one;-   (−)-1-(1-pyridin-3-ylpropyl)pyrrolidin-2-one;-   5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1,3-dihydro-2H-indol-2-one;-   1-[(6-chloropyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-(benzylamino)pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(2-aminopyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)pyrrolidin-2-one;-   1-[(2-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-[(2-propyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]pyrrolidin-2-one;-   1-[(6-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(1-benzoyl-6-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(7-oxido-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[2,3-c]pyridin-3-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[3,2-c]pyridin-3-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1,3,4-thiadiazol-2-ylmethyl)pyrrolidin-2-one;-   1-[(2-amino-1,3-thiazol-5-yl)methyl]pyrrolidin-2-one;-   1-(1,3-thiazol-5-ylmethyl)pyrrolidin-2-one;-   1-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-{[2-(dimethylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-{[2-(methylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(2-pyrrolidin-1-yl-1,3-thiazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   5-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1,3-thiazol-2(3H)-one;-   4-phenyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-7-yl]methyl}pyrrolidin-2-one;-   4-phenyl-1-[(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-7-yl)methyl]pyrrolidin-2-one;-   4-phenyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]methyl}pyrrolidin-2-one;-   4-propyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]methyl}pyrrolidin-2-one;-   4-phenyl-1-[(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]pyrrolidin-2-one;-   1-[(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4-phenylpyrrolidin-2-one;-   1-{[6-chloro-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl}-4-phenylpyrrolidin-2-one;-   1-[(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4-phenylpyrrolidin-2-one;-   1-[(2-fluoroindolizin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(1H-1,2,3-benzotriazol-1-ylmethyl)-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-chloro-1H-imidazo[4,5-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-phenyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(3H-imidazo[4,5-b]pyridin-3-ylmethyl)-4-propylpyrrolidin-2-one;-   1-[(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(3-chloro-7H-imidazo[4,5-c]pyridazin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-methyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-methyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-phenyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-fluoro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-bromo-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-chloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(2,3-dihydro-1H-indol-1-ylmethyl)-4-propylpyrrolidin-2-one;-   1-[(5-fluoro-2-phenyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-indole-2-carbonitrile;-   1-[(2-bromo-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2,5-dichloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-amino-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-(9H-purin-9-ylmethyl)pyrrolidin-2-one;-   1-{[6-(cyclopropylamino)-9H-purin-9-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(benzylamino)-9H-purin-9-yl]methyl}-4-propylpyrrolidin-2-one;-   4-propyl-1-{[6-(propylamino)-9H-purin-9-yl]methyl}pyrrolidin-2-one;-   1-{6-[(cyclopropylmethyl)amino]-9H-purin-9-yl}methyl)-4-propylpyrrolidin-2-one;-   4-propyl-1-[(6-pyrrolidin-1-yl-9H-purin-9-yl)methyl]pyrrolidin-2-one;-   1-[(5-bromo-3-phenyl-1H-pyrazolo[3,4-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-bromo-3-phenyl-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)pyrrolidin-2-one;-   1-(3,4-dihydroquinolin-1(2H)-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(8H-isothiazolo[5,4-b]indol-8-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(1H-1,2,4-triazol-1-ylmethyl)pyrrolidin-2-one;-   1-[(2,5-dichloro-1H-pyrrol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-pyrrol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;-   2-chloro-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;-   2-chloro-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-6-carbonitrile;-   4-propyl-1-[(2,5,6-trichloro-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one;-   1-[(2-chloro-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-5-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-6-nitro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-5-nitro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-6-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-bromo-2-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-bromo-2-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-6-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-5-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2,6-dichloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2,5-dichloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[2-chloro-6-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[2-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one;-   1-[(2-chloro-6-hydroxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(pyridin-4-ylmethyl)pyrrolidin-2-one, and-   1-[(2-chloro-5-hydroxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one.

viii) U.S. Pat. No. 4,696,943

The present invention relates to the novel compound(S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide.

ix) U.S. Pat. No. 4,696,942

The present invention relates to the novel compound,(R)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide

x) U.S. Pat. No. 5,334,720

According to this invention we provide novel compounds of the formula I,

wherein, R1, R2, R3 and R4, which may be the same or differentindependently represent hydrogen, C1-6 alkyl, phenyl or phenylsubstituted by one or more halogen, hydroxyl, nitro, amino, C1-6 alkylor C1-C6 alkoxy groups;

R5 and R6 independently represent hydrogen, C1-C6 alkyl or C3-C6cycloalkyl, or R5 and R6 together with the nitrogen form a C4-6 Nheterocycle;

m represents an integer from 1-2; and

n represents an integer from 1-3;

provided that,

two of the substituents R1, R2, R3 and R4 independently represent phenylor substituted phenyl and the other two independently represent hydrogenor C1-6 alkyl;

or a pharmaceutically acceptable acid addition salt thereof.

Pharmaceutically acceptable acid addition salts of the compounds offormula I include salts of mineral acids, for example, hydrohalic acids,e.g. hydrochloric or hydrobromic; or organic acids, e.g. formic, aceticor lactic acids. The acid may be polybasic, for example sulphuric,fumaric, maleic or citric acid.

This invention also relates to all stereoisomeric forms and opticalenantiomeric forms of the compounds of formula I.

In the compounds of formula I: alkyl groups which R1, R2, R3, R4, R5 andR6 may represent include methyl, ethyl, propyl, isopropyl, n-butyl,iso-butyl and s-butyl;

cycloalkyl groups which R5 and R6 may represent include cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl;

C1-6 alkoxy groups include methoxy, ethoxy and propoxy;

halogen groups include fluorine, chlorine, bromine or iodine;

We prefer compounds of formula I or a pharmaceutically acceptable acidaddition salt thereof, in which;

R1 is hydrogen, phenyl or substituted phenyl, preferably phenyl;

R2 is hydrogen, phenyl or substituted phenyl, preferably phenyl;

R3 is hydrogen, phenyl or substituted phenyl, preferably hydrogen;

R4 is hydrogen, phenyl or substituted phenyl, preferably hydrogen;

R5 is hydrogen, C1-3 alkyl or cyclopropyl, preferably hydrogen ormethyl;

R6 is hydrogen, C1-3 alkyl or cyclopropyl, preferably hydrogen ormethyl;

m represents an integer from 1-2 preferably 2;

n represents an integer from 1-2, preferably 1.

We especially prefer compounds of formula I in which R1 and R2 are bothphenyl.

We especially prefer compounds of formula I in which one of R5 and R6 ishydrogen and the other is hydrogen or methyl.

xi) International Patent Application Publication No. WO2005/054188

In one aspect the invention therefore provides a compound having theformula I or a pharmaceutically acceptable salt thereof,

wherein

RI is hydrogen, CI-20 alkyl, C3 23 cycloalkyl, halogen, hydroxy, alkoxy,aryloxy, ester, amido, cyano, nitro, amino, guanidine, amino derivative,alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl,arylsulfinyl, aryl or heterocycle; R2 is hydrogen, C1 20 alkyl, alkoxy,amino, halogen, hydroxy, ester, amido, nitro, cyano, carbamate, or aryl;

R3 is hydrogen, C1 20 alkyl, alkoxy, amino, halogen, hydroxy, ester,amido, nitro, cyano, carbamate, or aryl;

or R2 and R3 can form together with the imidazole ring the following1H-benzimidazole cycle

R4 is hydrogen, C1-20 alkyl, C2-12 alkenyl, C2-12 alkynyl, aryl, azido,alkoxycarbonylamino, arylsulfonyloxy or heterocycle; R4a is hydrogen orC1-20 alkyl; or R4 and R4a can form together a C3-8 cycloalkyl; R5 ishydrogen; or R4,

R4a and R5 can form together with the 2-oxo-1-pyrrolidine ring thefollowing 1, 3-dihydro-2H-indol-2-one cycle

R6 is hydrogen or C1 20 alkyl; R7 is hydrogen; or R6 and R7 are linkedtogether to form a C3-6 cycloalkyl; R8 is hydrogen, halogen, nitro,cyano, C1 20 alkyl or alkoxy; R9 is hydrogen, C1-20 alkyl, halogen,hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, aminoderivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl,alkylsulfinyl or arylsulfinyl;

RIO is hydrogen, C1 20 alkyl, halogen, hydroxy, alkoxy, aryloxy, ester,amido, cyano, nitro, amino, amino derivative, alkylthio, arylthio,alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl;

RI 1 is hydrogen, halogen, nitro, cyano, C1 20 alkyl or alkoxy; R12 ishydrogen or halogen;

R13 is hydrogen, nitro, halogen, heterocycle, amino, aryl, C1-20 alkylunsubstituted or substituted by halogen, or alkoxy unsubstituted orsubstituted by halogen; R14 is hydrogen, C1-20 alkyl or halogen;

R15 is hydrogen, C1 20 alkyl or halogen;

with the proviso that R4 is different from hydrogen when

N represents a group of formula

The asterisk * indicates the point of attachment of the substituents.

In a preferred embodiment, the invention concerns a compound having theformula I, their tautomers, geometrical isomers (including cis andtrans, Z and E isomers), enantiomers, diastereoisomers and mixturesthereof (including all possible mixtures of stereoisomers), orpharmaceutically acceptable salts thereof,

wherein

RI is hydrogen, C1-20 alkyl, C3-8 cycloalkyl, halogen, hydroxy, ester,amido, cyano, nitro, amino, guanidine, alkylthio, alkylsulfonyl,alkylsulfinyl, aryl or heterocycle; R2 is hydrogen, C1 20 alkyl,halogen, cyano, ester, carbamate or amido; R3 is hydrogen, cyano, C 1 20alkyl, halogen or ester; or R2 and R3 can form together with theimidazole ring the following 1H-benzimidazole cycle

R4 is hydrogen, C1 20 alkyl, C2 12 alkenyl or aryl; R4a is hydrogen;

R5 is hydrogen; or R4, R4a and R5 can form together with the2-oxo-1-pyrrolidine ring the following 1, 3-dihydro-2H-indol-2-one cycle

R6 is hydrogen or C 1 20 alkyl; R7 is hydrogen; or R6 and R7 are linkedtogether to form a C3-6 cycloalkyl; R8 is hydrogen; R9 is hydrogen, C1-20 alkyl, halogen or alkoxy; RIO is hydrogen, C1 20 alkyl, halogen orcyano; R11 is hydrogen; R12 is hydrogen or halogen; R13 is hydrogen,halogen, heterocycle or C1 20 alkyl;

R14 is hydrogen; R15 is hydrogen; with the proviso that R4 is differentfrom hydrogen when

represents a group of formula

The term “alkyl”, as used herein, represents saturated, monovalenthydrocarbon radicals having straight (unbranched) or branched or cyclicor combinations thereof and containing 1-20 carbon atoms, preferably1-10 carbon atoms, more preferably 1-4 carbon atoms; most preferredalkyl groups have 1-3 carbon atoms. Alkyl moieties may optionally besubstituted by 1 to 5 substituents independently selected from the groupconsisting of halogen, hydroxy, cyano, azido, aryloxy, alkoxy,alkylthio, alkanoylamino, arylcarbonylamino, aminocarbonyl,methylaminocarbonyl, dimethylaminocarbonyl or aryl. Usually alkylgroups, in the present case, are methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, t-butyl, 1-ethylpropyl, n-heptyl, 2,4,4-trimethylpentyl, n-decyl, chloromethyl, trifluoromethyl,2-bromo-2,2-difluoroethyl, 2,2, 2-trifluoroethyl, 3,3,3-trifluoropropyl, hydroxymethyl, cyanomethyl, azidomethyl,(acetylamino) methyl, (propionylamino) methyl, (benzoylamino) methyl,(4-chlorophenoxy) methyl, benzyl, 2-phenylethyl or 2-(methylthio) ethyl.Preferred alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, t-butyl, 1-ethylpropyl, 2,4, 4-trimethylpentyl, chloromethyl,trifluoromethyl, 2,2, 2-trifluoroethyl, hydroxymethyl, cyanomethyl,azidomethyl, (acetylamino) methyl, (propionylamino) methyl,(benzoylamino) methyl or 2-(methylthio) ethyl. More preferred alkylgroups are methyl, ethyl, n-propyl, i-propyl, n-butyl, azidomethyl ortrifluoromethyl. Most preferred alkyl groups are methyl or n-propyl.

The term “cycloalkyl”, as used herein, represents a monovalent group of3 to 8 carbon atoms, usually 3-6 carbon atoms derived from a saturatedcyclic hydrocarbon, which may be substituted by any suitable groupincluding but not limited to one or more moieties selected from groupsas described above for the alkyl groups. Preferred cycloalkyl groups arecyclopropyl and cyclohexyl.

The term “alkenyl” as used herein, represents straight, branched orcyclic unsaturated hydrocarbon radicals or combinations thereof havingat least one carbon-carbon double bond, containing 2-12 carbon atoms,preferably usually 2-4 carbon atoms. Alkenyl groups are being optionallysubstituted with any suitable group, including but not limited to one ormore moities selected from groups as described above for the alkylgroups. Usually an alkenyl group is ethenyl (vinyl) optionallysubstituted by 1 to 3 halogens. Preferred alkenyl group, in the presentcase, is 2,2-difluorovinyl.

The term “alkynyl” as used herein, represents straight, branched orcyclic hydrocarbon radicals or combinations thereof containing at leastone carbon-carbon triple bond, containing 2-12 carbon atoms, preferably2-6 carbon atoms, and being optionally substituted by any suitablegroup, including but not limited to one or more moities selected fromgroups as described above for the alkyl groups. Preferably an alkynylgroup is a halogenoalkynyl group (haloalkynyl group). Groups qualifiedby prefixes such as “s”, “i”, “t” and the like (e. g. “i-propyl”,“s-butyl”) are branched derivatives.

The term “aryl” as used herein, is defined as phenyl optionallysubstituted by 1 to 4 substituents independently selected from halogen,cyano, alkoxy, alkylthio, C1 3 alkyl or azido, preferably halogen orazido. Usually aryl groups, in the present case are phenyl,3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,3,4-difluorophenyl, 3, 5-difluorophenyl, 3-chloro-4-fluorophenyl, 2,3,4-trifluorophenyl, 2,4, 5-trifluorophenyl, 2,3, 5-trifluorophenyl, 3,4,5-trifluorophenyl, 3-azido-2,4-difluorophenyl or 3-azido-2,4,6-trifluorophenyl. Preferably, aryl groups are phenyl, 3-chlorophenyl,3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 3-chloro-4-fluorophenyl, 2,3, 4-trifluorophenyl,2,4, 5-trifluorophenyl, 2,3, 5-trifluorophenyl, 3,4, 5-trifluorophenylor 3-azido-2, 4-difluorophenyl. Most preferred aryl groups are phenyl,3-chlorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl, 2,4, 5-trifluorophenyl, 2,3, 5-trifluorophenyl, 3, 4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl.

The term “heterocycle”, as used herein, is defined as including anaromatic or non aromatic cycloalkyl moiety as defined above, having atleast one O, S and/or N atom interrupting the carbocyclic ringstructure. Heterocyclic ring moities can be optionally substituted byalkyl groups or halogens and optionally, one of the carbon of thecarbocyclic ring structure may be replaced by a carbonyl. Usuallyheterocycles are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-tetrahydrofuranyl, 1H-pyrrol-2-yl,1-methyl-1H-pyrrol-2-yl, 1H-pyrazol-2-yl, 1H-pyrazol-3-yl,4-chloro-1-methyl-1H-pyrazol-3-yl, 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl, 1, 2,3-thiadiazol-4-yl, 3,5-dimethyl-4-isothiazyl, 1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl,4-methyl-1H-imidazol-5-yl, or 2-methyl-1, 3-thiazol-4-yl. Preferredheterocycles are 1H-imidazol-2-yl, 1, 2,3-thiadiazol-4-yl,1H-pyrazol-3-yl, 2-furyl, 3-furyl, 2-thienyl, 1-methyl-1H-pyrrol-2-yl,1H-pyrrol-2-yl.

The term “halogen”, as used herein, includes an atom of chlorine,bromine, fluorine, iodine. Usually halogens are chlorine, bromine andfluorine. Preferred halogens are fluorine, bromine and chlorine.

The term “hydroxy”, as used herein, represents a group of formula-OH.

The term “alkoxy”, as used herein, represents a group of formula-ORawherein Ra is an alkyl group, as defined above. Preferred alkoxy groupis methoxy.

The term “aryloxy”, as used herein, represents a group of formula-ORbwherein Rb is an aryl group, as defined above. Preferred aryloxy groupis phenoxy.

The term “ester”, as used herein, represents a group of formula-COORCwherein Rc is an alkyl group or aryl group, as defined above. Preferredester group is methoxycarbonyl.

The term “amido”, as used herein, represents a group of formula-CONH2.

The term “amino”, as used herein, represents a group of formula-NH2.

The term “aminoderivative”, as used herein, represents an alkylamino oran arylamino group, wherein the terms “alkyl” and “aryl” are defined asabove.

The term “cyano”, as used herein, represents a group of formula-CN.

The term “nitro”, as used herein, represents a group of formula-NO2.

The term “azido”, as used herein, represents a group of formula-N3.

The term “guanidine”, as used herein, represents a group offormula-NHC(═NH) NH2.

The term “alkylthio”, as used herein, represents a group of formula-SRdwherein

Rd is an alkyl group, as defined above. One alkylthio group ismethylthio.

The term “alkylsulfonyl”, as used herein, represents a group offormula-S(═O) 2Re wherein Re is an alkyl group, as defined above. Onealkylsulfonyl group is methylsulfonyl.

The term “alkylsulfinyl”, as used herein, represents a group offormula-S(═O) Rf wherein Rf is an alkyl group, as defined above. Onealkylsulfinyl group is methylsulfinyl.

The term “arylthio”, as used herein, represents a group of formula-SRgwherein Rg is an aryl group, as defined above.

The term “arylsulfonyl”, as used herein, represents a group of theformula-S(═O) 2Rh wherein Rh is an aryl group, as defined above.

The term “arylsulfinyl”, as used herein, represents a group of theformula-S(═O) Ri wherein Ri is an aryl group, as defined above.

The term “carbamate”, as used herein, represents a group offormula-N(H)C(O) OR1, wherein Ri is an alkyl or an aryl, as definedabove. Usually carbamate groups are (propoxycarbonyl) amino or(benzyloaxycarbonyl) amino. One carbamate group is (benzyloaxycarbonyl)amino.

The term “alkanoylamino”, as used herein, represents a group of theformula-NHC(═O) Rk wherein Rk is an alkyl group, as defined above.

The term “(arylcarbonyl) amino”, as used herein, represents a group ofthe formula-NHC(═O) Rm wherein Rm is an aryl group, as defined above.One (arylcarbonyl) amino is benzoylamino.

Usually, RI is hydrogen; Cl lo alkyl unsubstituted or substituted byhalogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; hydroxy;C3-6 cycloalkyl; halogen; ester; amido; nitro; cyano; amino; phenyl;alkylthio; alkylsulfonyl; alkylsulfinyl; heterocycle unsubstituted orsubstituted by alkyl groups; or guanidine.

In some embodiments, RI is hydrogen; methyl; ethyl; i-propyl; n-propyl;cyclopropyl; n-butyl; i-butyl; t-butyl; 1-ethylpropyl; 2,4,4-trimethylpentyl; hydroxymethyl; chloromethyl; trifluoromethyl; 2,2,2-trifluoroethyl; cyanomethyl; 2-(methylthio) ethyl; chloro; bromo;nitro; cyano; amino; aminocarbonyl; methoxycarbonyl; methylthio;methylsulfinyl; methylsulfonyl; phenyl; 2-furyl; 3-furyl;1H-pyrrol-2-yl; 1-methyl-1H-pyrrol-2-yl; 2-thienyl; 1H-pyrazol-3-yl; 1,2,3-thiadiazol-4-yl or 1H-imidazol-2-yl. More preferably, RI ishydrogen; methyl; ethyl; i-propyl; n-propyl; n-butyl; methylthio; nitro;cyano; amino; chloro or 1H-pyrrol-2-yl. Most preferably, RI is hydrogen;methyl; methylthio; nitro; cyano; amino or chloro.

Usually, R2 is hydrogen; C1 4 alkyl unsubstituted or substituted byhydroxy, alkanoylamino or benzoylamino; halogen; ester; cyano; alkylcarbamate; [(N-methoxy-N-methyl) amino] carbonyl. Preferably, R2 ishydrogen; methyl; hydroxymethyl; (acetylamino) methyl; (propionylamino)methyl; (benzoylamino) methyl; [(benzyloxy) carbonyl] amino; chloro orcyano. In some embodiments, R2 is hydrogen; chloro or cyano.

Usually, R3 is hydrogen; C1 4 alkyl unsubstituted or substituted byhydroxy; halogen; ester or cyano. In some embodiments, R3 is hydrogen;hydroxymethyl; chloro; cyano.

In some embodiments, R3 is hydrogen or cyano. In some embodiments R3 ishydrogen.

Usually, R4 is hydrogen; C1 4 alkyl tlnsubstituted or substituted byhalogens; C2 4 alkenyl substituted by halogens or phenyl groupunsubstituted or substituted by azido or/and halogens. Preferably, R4 ishydrogen; n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl;3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl;3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3, 4-trifluorophenyl;2,4, 5-trifluorophenyl; 2,3, 5-trifluorophenyl; 3,4, 5-trifluorophenyl;3-azido-2,4-difluorophenyl or 3-azido-2,4, 6-trifluorophenyl. Morepreferably, R4 is hydrogen; n-propyl; 2,2-difluorovinyl; phenyl;3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl; 2,4, 5-trifluorophenyl; 2,3, 5-trifluorophenyl; 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. Most preferably, R4 isn-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl;3,5-difluorophenyl; 2,3, 4-trifluorophenyl; 2,4, 5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4, 5-trifluorophenyl or 3-azido-2,4-difluorophenyl.

Usually, R4a is hydrogen.

Usually, R5 is hydrogen.

Usually, R6 is hydrogen or C1-1-0 alkyl unsubstituted or substituted byhydroxy or azido. Preferably, R6 is hydrogen or azidomethyl. Morepreferably R6 is hydrogen.

Usually R7 is hydrogen.

In other embodiments, R6 and R7 are linked to form a cyclopropyl.

In other embodiments, R2 and R3 can form together with the imidazolering the following 1H-benzimidaole cycle

Usually, R8 is hydrogen.

Usually, R9 is hydrogen; halogen; 1-3 alkyl or alkoxy. In someembodiments, R9 is hydrogen; methyl; chloro or methoxy. In someembodiments R9 is hydrogen.

Usually, RIO is hydrogen; halogen; cyano; C1 3 alkyl unsubstituted orsubstituted by halogens; or alkoxy. In some embodiments, RIO is methyl;hydrogen; trifluoromethyl; fluoro; cyano or methoxy. In some embodimentsR10 is hydrogen; trifluoromethyl; fluoro or cyano.

Usually, RI 1 is hydrogen.

In other embodiments, R4, R4a and R5 can form together with the2-oxo-1-pyrrolidine ring the following 1, 3-dihydro-2H-indol-2-one cycle

Usually, R12 is hydrogen or halogen. In some embodiments R12 ishydrogen; chloro or fluoro. In some embodiments R12 is hydrogen.

Usually, R13 is hydrogen; C1 3 alkyl; halogen or thiazolyl unsubstitutedor substituted by alkyl groups, such as methylthiazolyl. In someembodiments R13 is hydrogen; chloro; bromo or methyl. In someembodiments R13 is chloro; bromo or methyl.

Usually R14 is hydrogen.

Usually, R15 is hydrogen.

In a general embodiment of the invention, the compounds of formula I, orpharmaceutically acceptable salts thereof, are those wherein

RI is selected from hydrogen; C1 lo alkyl unsubstituted or substitutedby halogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; C3 6cycloalkyl; halogen; ester; amido; nitro; cyano; amino; phenyl;alkylthio; alkylsulfonyl; alkylsulfinyl; heterocycle unsubstituted orsubstituted by alkyl group; or guanidine; R2 is selected from hydrogen;C 1-4 alkyl unsubstituted or substituted by hydroxy, alkanoylamino orbenzoylamino; halogen; ester; cyano; alkyl carbamate or[(N-methoxy-N-methyl) amino] carbonyl.

R3 is selected from hydrogen; C1 4 alkyl unsubstituted or substituted byhydroxy; halogen; ester or cyano; R4 is selected from hydrogen; C1 4alkyl unsubstituted or substituted by halogens; C2 4 alkenyl substitutedby halogens or phenyl group unsubstituted or substituted by azido or/andhalogens;

R4a is hydrogen; R5 is hydrogen; R6 is selected from hydrogen or C 1-10alkyl unsubstituted or substituted by hydroxy or azido;

R7 is hydrogen; or R6 and R7 can be linked to form a cyclopropyl; or R2and R3 can form together with the imidazole ring the following1H-benzimidazole cycle

R8 is hydrogen; R9 is selected from hydrogen; halogen; C1-3 alkyl;alkoxy;

R10 is selected from hydrogen; halogen; cyano or Cil alkyl unsubstitutedor substituted by halogens; or alkoxy; R1 is hydrogen; or R4, R4a and R5can form together with the 2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one cycle

R12 is selected from hydrogen or halogen; R13 is selected from hydrogen;CI-3 alkyl; halogen; thiazolyl unsubstituted or substituted by alkylgroups, such as methylthiazolyl; R14 is hydrogen; R15 is hydrogen; withthe proviso that R4 is different from hydrogen when

represents a group of formula

In an embodiment of the invention, the compounds of formula I, orpharmaceutically acceptable salt thereof, are those wherein

RI is selected from hydrogen; methyl; ethyl; i-propyl; n-propyl;cyclopropyl; n-butyl; i-butyl; t-butyl; 1-ethylpropyl; 2,4,4-trimethylpentyl; trifluoromethyl; 2,2, 2-trifluoroethyl;hydroxymethyl; chloromethyl; cyanomethyl; 2-(methylthio) ethyl; chloro;bromo; nitro; cyano; amino; aminocarbonyl; methoxycarbonyl; methylthio;methylsulfinyl; methylsulfonyl; phenyl; 2-furyl; 3-furyl;1H-pyrrol-2-yl; 1-methyl-1H-pyrrol-2-yl; 2-thienyl; 1H-pyrazol-3-yl; 1,2, 3-thiadiazol-4-yl; or 1H-imidazol-2-yl; R2 is selected from hydrogen;methyl; hydroxymethyl; (acetylamino) methyl; (propionylamino) methyl;(benzoylamino) methyl; (benzyloxycarbonyl) amino; chloro; or cyano; R3is selected from hydrogen; hydroxymethyl; chloro; cyano; or R2 and R3can form together with the imidazole ring the following 1H-benzimidazolecycle

R8 is hydrogen; R9 is selected from hydrogen; methyl; choro; methoxy;R10 is selected from methyl; hydrogen; trifluoromethyl; fluoro; cyano;or methoxy; R is hydrogen; R4 is selected from hydrogen; n-propyl;2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl;4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl;3-chloro-4-fluorophenyl; 2,3, 4-trifluorophenyl; 2,4, 5-trifluorophenyl;2,3, 5-trifluorophenyl; 3,4, 5-trifluorophenyl;3-azido-2,4-difluorophenyl; or 3-azido-2,4, 6-trifluorophenyl. R4a ishydrogen; R5 is hydrogen; or R4, R4a and R5 can form together with the2-oxo-1-pyrrolidine ring the following 1, 3-dihydro-2H-indol-2-one cycle

R12 is selected from hydrogen; chloro; fluoro; R13 is selected fromhydrogen; chloro; bromo; methyl; R14 is hydrogen; R15 hydrogen; R6 isselected from hydrogen; azidomethyl; R7 is hydrogen; or R6 and R7 arelinked to form a cyclopropyl; with the proviso that R4 is different fromhydrogen when

represents a group of formula

In one embodiment of the invention, the compounds of formula I, orpharmaceutically acceptable salt thereof, are those wherein

RI is selected from hydrogen; methyl; ethyl; i-propyl; n-propyl;n-butyl; methylthio; nitro; cyano; amino; chloro; or 1H-pyrrol-2-yl; R2is selected from hydrogen; chloro; cyano; R3 is selected from hydrogen;cyano; or R2 and R3 can form together with the imidazole ring thefollowing 1H-benzimidazole cycle

R8 is hydrogen; R9 is hydrogen;

R10 is selected from hydrogen; trifluoromethyl; fluoro; cyano;

RI 1 is hydrogen; R4 is selected from hydrogen; n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl;4-fluorophenyl; 3, 5-difluorophenyl; 3,4-difluorophenyl;3-chloro-4-fluorophenyl; 2,3, 4-trifluorophenyl; 2,4, 5-trifluorophenyl;2,3, 5-trifluorophenyl; 3,4, 5-trifluorophenyl; or 3-azido-2,4-difluorophenyl; R4a is hydrogen; R5 is hydrogen; or R4, R4a and R5 canform together with the 2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one cycle

wherein R12 is hydrogen; R13 is selected from methyl; chloro; bromo; R14is hydrogen; R15 hydrogen; R6 is hydrogen; R7 is hydrogen; with theproviso that R4 is different from hydrogen when

R11 represents a group of formula

In one embodiment of the invention, the compounds of formula I, orpharmaceutically acceptable salt thereof, are those wherein

RI is selected from hydrogen; methyl; methylthio; nitro; cyano; amino;chloro; R2 is selected from hydrogen; chloro; cyano; R3 is hydrogen; R4is selected from n-propyl; 2, 2-difluorovinyl; phenyl; 3-chlorophenyl;3-fluorophenyl; 3,5-difluorophenyl; 2,3, 4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3, 5-trifluorophenyl; 3,4, 5-trifluorophenyl;3-azido-2,4-difluorophenyl; R4a is hydrogen;

R5 is hydrogen; or R4, R4a and R5 can form together with the2-oxo-1-pyrrolidine ring the following 1, 3-dihydro-2H-indol-2-one cycle

R12 is hydrogen; R13 is selected from chloro; bromo; methyl; R14 ishydrogen;

R15 hydrogen; R6 is hydrogen; R7 is hydrogen.

In some embodiments, compounds are: 1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;4-(3-azido-2, 4, 6-trifluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(IH-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; (+)-4-(3-azido-2,4-difluorophenyl)-1-(IH-imidazol-1-ylmethyl) pyrrolidin-2-one;1-[(2-ethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-isopropyl-1H-imidazol-1-yl) methyl]-4-propylpyrrolidin-2-one;1-[(2-methyl-IH-imidazol-1-yl) methyl]-4-propylpyrrolidin-2-one;1-[(2-phenyl-1H-imidazol-1-yl) methyl]-4-propylpyrrolidin-2-one;4-propyl-1-[(2-propyl-1H-imidazol-1-yl) methyl] pyrrolidin-2-one;(+)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;1-{[2-(methylthio)-1H-imidazol-1-yl] methyl}-4-propylpyrrolidin-2-one;1-{[2-(methylsulfinyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-tert-butyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[1-(1H-imidazol-1-yl) cyclopropyl]pyrrolidin-2-one; 1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;1-{[2-(methylsulfonyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxamide;4-(4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(3, 4, 5-trifluorophenyl) pyrrolidin-2-one;4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3-chloro-4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(4-chlorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2, 3, 4-trifluorophenyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2, 3,5-trifluorophenyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2, 4,5-trifluorophenyl) pyrrolidin-2-one;1-{[2-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;methyl 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxylate; 1-[(2-nitro-IH-imidazol-1-yl)methyll-4-(3,4,5-trifluorophenyl) pyrrolidin-2-one; 1-{[2-oxo-4-(3, 4,5-trifluorophenyl) pyrrolidin-1-yl] methyl}-1H-imidazole-2-carbonitrile;1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2,4-dichloro-IH-imidazol-1-yl) methyl]-4-(3, 4, 5-trifluorophenyl)pyrrolidin-2-one; 1-[(5-chloro-1H-imidazol-1-yl) methyl]-4-(3, 4,5-trifluorophenyl) pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl) pyrrolidin-1-yl] methyl}-1H-imidazole-4-carbonitrile;1-{[2-oxo-4-(3,4, 5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; 1-{[2-oxo-4-(2,3, 5-trifluorophenyl) pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; (−)-1-{[2-oxo-4-(2, 3,4-trifluorophenyl) pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(+)-1-{[2-oxo-4-(2, 3,4-trifluorophenyl) pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; (−)-1-{[2-oxo-4-(2,3,4-trifluorophenyl) pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (+)-1-{[2-oxo-4-(2, 3,4-trifluorophenyl)-1-pyrrolidinyl] methyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(+)-1-{[2-oxo-4-(3,4, 5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (+)-1-{[2-oxo-4-(2,4, 5-trifluorophenyl) pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (−)-1-{[2-oxo-4-(2,4,5-trifluorophenyl) pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (−)-1-{[2-oxo-4-(2, 3,5-trifluorophenyl) pyrrolidin-1-ylmethyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(3, 4, 5=trifluorophenyl) pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; 1-{[2-oxo-4-(2, 3,5-trifluorophenyl) pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-{[2-oxo-4-(2, 3,5-trifluorophenyl)pyrrolidin-methyl}-1H-imidazole-5-carbonitrile;phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-methyl-IH-imidazol-1-yl) methyl]-4-propylpyrrolidin-2-one;1[(5-phenyl-1H-imidazol-1-yl) methyl]-4-propylpyrrolidin-2-one;1-[(2-ethyl-5-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2,5-dimethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-chloro-IH-imidazol-1-yl) methyll-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[2-azido-1-(1H-imidazol-1-yl)ethyl]-4-propylpyrrolidin-2-one; 1-[(4-chloro-IH-imidazol-1-yl)methyll-4-(3,4,5-trifluorophenyl) pyrrolidin-2-one;1-[(2-bromo-4,5-dichloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;(+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-{[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[4-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; benzyl1-[(2-oxo-4-propylpyrrolidin-1-yl) methyl]-1H-imidazol-5-ylcarbamate;N-[(1-{[2-oxo-4-(3, 4,5-trifluorophenyl) pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl) methyl] acetamide; N-[(1-{[2-oxo-4-(3, 4,5-trifluorophenyl) pyrrolidin-1-yl] methyl}-1H-imidazol-5-yl) methyl]benzamide; N-1 (1-1 [2-oxo-4-(3, 4, 5-trifluorophenyl)pyrroldin-1-yl]methyl}-1H-imidazol-5-yl) methyl] propanamide;1-(IH-benzimidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl-1-[(2-propyl-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one;1-[(2-isopropyl-1H-benzimidazol-1-yl) methyl]-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl] methyl}pyrrolidin-2-one; 1-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-amino-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[2-(chloromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; {1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazol-2-yl} acetonitrile;1-[(5-methoxy-1H-benzimidazol-1-yl) methyl]-4-propylpyrrolidin-2-one;1[(5-methyl-1H-benzimidazol-1-yl) methyl]-4-propylpyrrolidin-2-one;1-[(5, 6-dimethyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[2-isopropyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(6-chloro-IH-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-propyl-1H-benzimidazole-5-carbonitrile;1-{[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl] methyl}pyrrolidin-2-one; 1-[(5-fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[6-methyl-2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(6-methoxy-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;2-butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-IH-benzimidazole-5-carbonitrile; 1-{[2-[2-(methylthio)ethyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(5-fluoro-2-isobutyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[5-fluoro-2-(2, 4, 4-trimethylpentyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;2-cyclopropyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-(1H-pyrazol-3-yl)-1H-benzimidazole-5-carbonitrile;1-[(2-cyclopropyl-5-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[2-(3-furyl)-6-methoxy-1H-benzimidazol-1-ylmethyl}-4-propylpyrrolidin-2-one;1-[(2-cyclopropyl-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-isopropyl-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-(1, 2,3-thiadiazol-4-yl)-1H-benzimidazole-5-carbonitrile;1-{[2-(1H-imidazol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[5-fluoro-2-(2, 2,2-trifluoroethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[2-(1-ethylpropyl)-6-methoxy-IH-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[6-methoxy-2-(1-methyl-1H-pyrrol-2-yl)-IH-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[2-(2-furyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;4-propyl-1-{[2-thien-2-yl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;1-{[2-(3-furyl)-5-(trifluoromethyl)-IH-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[2-cyclopropyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(1H-pyrrol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl} pyrrolidin-2-one; 1-(IH-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 4-fluoro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 4-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one; 1-[(2-oxo-2, 3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile; and 1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) methyl]-1H-imidazole-5-carbonitrile.

In some embodiments, compounds are: 1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one, 1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; (−)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-[(2-ethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl) methyl]-4-propylpyrrolidin-2-one;4-propyl-1-[(2-propyl-1H-imidazol-1-yl) methyl] pyrrolidin-2-one;(+)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-(1 H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;4-(4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(3, 4, 5-trifluorophenyl) pyrrolidin-2-one;4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3-chloro-4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(4-chlorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2, 3, 4-trifluorophenyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2, 3,5-trifluorophenyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2, 4,5-trifluorophenyl) pyrrolidin-2-one;1-[(2-nitro-1H-imidazol-1-yl) methyl]-4-(3, 4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3, 4, 5-trifluorophenyl) pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile;1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-1(5-chloro-IH-imidazol-1-yl) methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3, 4,5-trifluorophenyl) pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; 1-{[2-oxo-4-(3, 4,5-trifluorophenyl) pyrrolidin-1-yl] methyl}-1H-imidazole-5-carbonitrile;(+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (+);1-{[2-oxo-4-(3, 4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;1-[(2-chloro-1H-imidazol-1-yl) methyl]-4-(3, 4, 5-trifluorophenyl)pyrrolidin-2-one; 1-[2-azido-1-(1H-imidazol-1-yl)ethyl]-4-propylpyrrolidin-2-one; 1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; (+)-1-{[2-oxo-4-(3, 4,5-trifluorophenyl) pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-propyl-1H-benzimidazole-5-carbonitrile;1-{[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;1-[(5-fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;2-butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;1-[(5-fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one;1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile.

In some embodiments, compounds are:1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; (−)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;(+)-4-(3-azido-2, 4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl) pyrrolidin-2-one;4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3,5-difluoromethyl)-1-(IH-imidazol-1-ylmetliyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2, 3,4-trifluorophenyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2, 3,5-trifluorophenyl) pyrrolidin-2-one;1-H-imidazol-1-ylmethyl)-4-(2, 4,5-trifluorophenyl) pyrrolidin-2-one;1-[(2-nitro-1H-imidazol-1-yl) methyl]-4-(3, 4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3, 4, 5-trifluorophenyl) pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile; 1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3, 4,5-trifluorophenyl)pyrrolidin-2-one;(+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl) methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one 1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; (+)-1-1[2-oxo-4-(3,4,5-trifluorophenyl) pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;5-bromo-1-(1H-imidazol-1-ylmethyl)-1, 3-dihydro-2H-indol-2-one;5-chloro-1-(1H-imidazol-1-ylmethyl)-1, 3-dihydro-2H-indol-2-one;1-(1H-imidazol-1-ylmethyl)-5-methyl-1, 3-dihydro-2H-indol-2-one;1-[(5-chloro-2-oxo-2, 3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile.

Some compounds are: (−)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;(+)-4-(3-azido-2, 4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one.

The acid addition salt form of a compound of formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, a hydrohalicsuch as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric andthe like; or an organic acid, such as, for example, acetic,trifluoroacetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic,succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclic, salicylic,p-aminosalicylic, pamoic and the like.

The compounds of formula I containing acidic protons may be convertedinto their therapeutically active, non-toxic base addition salt forms,e. g. metal or amine salts, by treatment with appropriate organic andinorganic bases. Appropriate base salt forms include, for example,ammonium salts, alkali and earth alkaline metal salts, e. g. lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e. g. N-methyl-D-glucamine, hydrabamine salts, and saltswith amino acids such as, for example, arginine, lysine and the like.

Conversely said salt forms can be converted into the free forms bytreatment with an appropriate base or acid.

Compounds of the formula I and their salts can be in the form of asolvate, which is included within the scope of the present invention.Such solvates include for example hydrates, alcoholates and the like.

Many of the compounds of formula I and some of their intermediates haveat least one stereogenic center in their structure. This stereogeniccenter may be present in a R or a S configuration, said R and S notationis used in correspondence with the rules described in Pure Appl. Chem.,45 (1976) 11-30.

The invention also relates to all stereoisomeric forms such asenantiomeric and diastereoisomeric forms of the compounds of formula Ior mixtures thereof (including all possible mixtures of stereoisomers).

Some of the compounds of formula I may also exist in tautomeric forms.Such forms although not explicitly indicated in the above formula areintended to be included within the scope of the present invention.

In another preferred embodiment, the present invention concerns alsocompounds of formula IA and their tautomeric form IB

With respect to the present invention reference to a compound orcompounds is intended to encompass that compound in each of its possibleisomeric forms and mixtures thereof, unless the particular isomeric formis referred to specifically. Compounds according to the presentinvention may exist in different polymorphic forms. Although notexplicitly indicated in the above formula, such forms are intended to beincluded within the scope of the present invention.

The invention also includes within its scope pro-drug forms of thecompounds of formula I and its various sub-scopes and sub-groups.

xii) U.S. Patent Application Publication No. 20090018148

In one aspect the invention provides compounds having formula I, theirenantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers), or pharmaceutically acceptablesalts thereof,

wherein

R1 is hydrogen or C1-6 alkyl;

R2 is hydrogen or C1-4 alkyl;

R3 is a group of formula —CHR5R6 or a benzyl group;

R4 is C1-8 alkyl optionally substituted by alkoxycarbonyl, C3-6cycloalkyl, aryl or heterocycle;

R5 is C2-4 alkyl;

R6 is C2-4 alkyl, amido or —COOR7;

R7 is C1-4 alkyl;

In one aspect, the invention provides compounds:

When R1 is hydrogen, R2 is methyl, R3 is CHR5R6, R6 is ethoxycarbonyland R5 is ethyl, then R4 is different from methyl, n-propyl, i-propyl,n-pentyl, n-heptyl, 3-bromobenzyl, 4-chlorobenzyl, 4-methylbenzyl or2-phenylethyl;

When R1 is hydrogen, R2 is methyl, R3 is benzyl, then R4 is differentfrom i-propyl, n-butyl, 3-methylbutyl, benzyl, phenylethyl-, or3-phenylpropyl;

When R1 and R2 are methyl, R3 is benzyl, R4 is different from methyl,3-methylbutyl, benzyl, 3-phenylpropyl or 4-chlorophenylmethyl;

Finally8-(2-chloro-benzylsulfanyl)-3-methyl-7-octyl-3,7-dihydro-purine-2,6-dioneis considered.

Usually when R3 is a benzyl group, then R4 is C1-8 alkyl optionallysubstituted by alkoxycarbonyl.

Usually when R3 is a group of formula CHR5R6, then R4 is C1-8 alkyloptionally substituted by C3-6 cycloalkyl, aryl or heterocycle.

The term “alkyl”, as used herein, is a group which represents saturated,monovalent hydrocarbon radicals having straight (unbranched) or branchedmoieties, or combinations thereof, and containing 1-8 carbon atoms,preferably 1-6 carbon atoms; more preferably alkyl groups have 1-4carbon atoms. Alkyl moieties may optionally be substituted by 1 to 5substituents independently selected from the group consisting ofhydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl, acyl, aryl orheterocycle. Alkyl moieties may be optionally substituted by acycloalkyl as defined hereafter. Preferred alkyl groups according to thepresent invention are methyl, cyanomethyl, ethyl, 2-ethoxy-2-oxoethyl,2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl,n-butyl, i-butyl, n-pentyl, 3-pentyl, n-hexyl, cyclohexylmethyl, benzyl,2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl,2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl or(5-nitro-2-furyl)methyl. More preferred alkyl groups are methyl, ethyl,cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropyl, 2-propynyl,n-butyl, 3-pentyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl or(5-nitro-2-furyl)methyl. Most preferred alkyl groups are methyl, ethyl,3-methoxybenzyl, 3-nitrobenzyl or (5-nitro-2-furyl)methyl.

The term “cycloalkyl”, as used herein, represents a monovalent group of3 to 8, preferably 3 to 6 carbon atoms derived from a saturated cyclichydrocarbon, which may be substituted by any suitable group includingbut not limited to one or more moieties selected from groups asdescribed above for the alkyl groups. Preferred cycloalkyl groupaccording to the present invention is cyclohexyl.

The term “aryl” as used herein, is defined as a phenyl group optionallysubstituted by 1 to 4 substituents independently selected from halogen,amino, nitro, alkoxy or aminosulfonyl. Preferred aryl groups are phenyl,2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-methoxyphenyl,3-nitrophenyl, 3-aminophenyl or 4-(aminosulfonyl)phenyl.

The term “phenyl”, as used herein, represents an aromatic hydrocarbongroup of formula —C6H5.

The term “benzyl group”, as used herein, represents a group of formula—CH2-aryl. Preferred benzyl groups are benzyl, 2-bromobenzyl,3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl,3-aminobenzyl or 4-(aminosulfonyl)benzyl. More preferred benzyl groupsare benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl or3-aminobenzyl. In some embodiments alkyl groups are 3-methoxybenzyl or3-nitrobenzyl.

The term “halogen”, as used herein, represents an atom of fluorine,chlorine, bromine, or iodine. In some embodiments the halogen isbromine.

The term “hydroxy”, as used herein, represents a group of formula —OH.

The term “cyano”, as used herein, represents a group of formula —CN.

The term “amino”, as used herein, represents a group of formula —NH2.

The term “ethynyl”, as used herein, represents a group of formula —C≡CH.

The term “alkoxy”, as used herein, represents a group of formula —ORawherein

Ra is an alkyl group, as defined above. In some embodiments the alkoxygroup is methoxy.

The term “nitro”, as used herein, represents a group of formula —NO2.

The term “amido”, as used herein, represents a group of formula—C(═O)NH2.

The term “acyl”, as used herein, represents a group of formula —C(═O)Rbwherein Rb is an alkyl group, as defined here above. In some embodimentsthe acyl group is acetyl (—C(═O)Me).

The term “alkoxycarbonyl (or ester)”, as used herein, represents a groupof formula —COORc wherein Rc is an alkyl group; with the proviso that Rcdoes not represent an alkyl alpha-substituted by hydroxy. In someembodiments the alkoxycarbonyl group is ethoxycarbonyl.

The term “heterocycle”, as used herein, represents a 5-membered ringcontaining one or two heteroatoms selected from 0 or N. The heterocyclemay be substituted by one or two C1-4 alkyl or nitro. In someembodiments the heterocycles are (3,5-dimethylisoxazol-4-yl) or(5-nitro-2-furyl). Most preferred heterocycle is (5-nitro-2-furyl).

Generally R1 is hydrogen or C1-6 alkyl. Usually R1 is hydrogen or C1-6alkyl optionally substituted by hydroxy, alkoxy, cyano, ethynyl,alkoxycarbonyl or acyl. In some embodiments R1 is hydrogen, methyl,cyanomethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl,3-hydroxypropyl, 2-propynyl, n-pentyl or n-hexyl. In some embodiments R1is hydrogen, methyl, cyanomethyl, 2-methoxyethyl, n-propyl,3-hydroxypropyl or 2-propynyl. In some embodiments R1 is hydrogen.

Generally R2 is hydrogen or C1-4 alkyl. Usually R2 is hydrogen orunsubstituted C1-4 alkyl. In some embodiments R2 is hydrogen, methyl orn-butyl. In some embodiments, R2 is methyl.

Generally R3 is a group of formula —CHR5R6 or a benzyl group. In someembodiments R3 is 3-pentyl, 1-(aminocarbonyl)propyl,1-(ethoxycarbonyl)propyl or 3-bromobenzyl. In some embodiments R3 is1-(ethoxycarbonyl)propyl. Generally R4 is C1-8 alkyl optionallysubstituted by alkoxycarbonyl, C3-6 cycloalkyl, aryl or heterocycle.Usually R4 is C1-8 alkyl optionally substituted by cyclohexyl, phenyl,bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl,aminosulfonylphenyl, 3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl orethoxycarbonyl. In some embodiments R4 is n-butyl, i-butyl, n-pentyl,n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl, 3-bromobenzyl,4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl,4-(aminosulfonyl)benzyl, 1-phenylethyl, 2-phenylethyl,(3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl)methyl or1-(ethoxycarbonyl)propyl. In some embodiments R4 is n-butyl, n-hexyl,benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl,(3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl)methyl or1-(ethoxycarbonyl)propyl. In some embodiments R4 is 3-methoxybenzyl,3-nitrobenzyl or (5-nitro-2-furyl)methyl.

Generally R5 is C2-4 alkyl. Usually R5 is unsubstituted C2-4 alkyl. Insome embodiments R5 is ethyl.

Generally R6 is C2-4 alkyl, amido or —COOR7. Usually R6 is unsubstitutedC2-4 alkyl, amido or —COOR7. In some embodiments R6 is ethyl, amido orethoxycarbonyl. In some embodiments R6 is ethoxycarbonyl.

Generally R7 is C1-4 alkyl. Usually R7 is unsubstituted C1-4 alkyl. Insome embodiments, R7 is ethyl.

Usually the invention provides compounds having formula I, theirenantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers), or pharmaceutically acceptablesalts thereof,

wherein

R1 is hydrogen, C1-6 alkyl optionally substituted by hydroxy, alkoxy,cyano, ethynyl, alkoxycarbonyl or acyl;

R2 is hydrogen or unsubstituted C1-4 alkyl;

R3 is a group of formula CHR5R6 or a benzyl group;

R4 is C1-8 alkyl optionally substituted by cyclohexyl, phenyl,bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl,aminosulfonylphenyl, 3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl orethoxycarbonyl;

R5 is unsubstituted C2-4 alkyl;

R6 is unsubstituted C2-4 alkyl, amido or COOR7;

R7 is unsubstituted C1-4 alkyl;

with the proviso that when R1 is hydrogen, R2 is methyl, R3 is CHR5R6,R6 is ethoxycarbonyl and R5 is ethyl, then R4 is different fromn-propyl, i-propyl, n-pentyl, n-heptyl, 3-bromobenzyl, 4-chlorobenzyl,4-methylbenzyl or 2-phenylethyl.

In the above embodiment, sometimes, when R3 is a benzyl group, then R4is C1-8 alkyl optionally substituted by alkoxycarbonyl.

In the above embodiment, sometimes, when R3 is a group of formulaCHR5R6, then R4 is C1-8 alkyl optionally substituted by C3-6 cycloalkyl,aryl or heterocycle.

In one embodiment,

R1 is hydrogen, methyl, cyanomethyl, 2-ethoxy-2-oxoethyl,2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl,n-pentyl or n-hexyl;

R2 is hydrogen, methyl or n-butyl;

R3 is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or3-bromobenzyl;

R4 is n-butyl, i-butyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl,2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl,2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl,(5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl;

with the proviso that when R1 is hydrogen, R2 is methyl and R3 is1-(ethoxycarbonyl)propyl, then R4 is different from n-pentyl,3-bromobenzyl or 2-phenylethyl.

In the above embodiment, sometimes, when R3 is 3-bromobenzyl, then R4 isC1-8 alkyl optionally substituted by alkoxycarbonyl.

In the above embodiment, sometimes, when R3 is 3-pentyl,1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl, then R4 isdifferent from 1-(ethoxycarbonyl)propyl.

In a more preferred embodiment, R1 is hydrogen, methyl, cyanomethyl,2-methoxyethyl, n-propyl, 3-hydroxypropyl or 2-propynyl;

R2 is methyl;

R3 is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or3-bromobenzyl;

R4 is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl,(5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl;

with the proviso that when R1 is hydrogen, R2 is methyl and R3 is1-(ethoxycarbonyl)propyl, then R4 is different from 3-bromobenzyl.

In the above embodiment, sometimes, when R3 is 3-bromobenzyl, then R4 is1-(ethoxycarbonyl)propyl;

In the above embodiment, sometimes, when R3 is 3-pentyl,1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl, then R4 isdifferent from 1-(ethoxycarbonyl)propyl;

In one embodiment, R1 is hydrogen; R2 is methyl; R3 is1-(ethoxycarbonyl)propyl; and R4 is 3-methoxybenzyl, 3-nitrobenzyl or(5-nitro-2-furyl)methyl.

A further embodiment consists in compounds wherein R2 is methyl, R3 is agroup of formula CHR5R6 with R5 being C2-4 alkyl, R6 being amido orCOOR7 and R7 being methyl or ethyl.

In some embodiments, compounds are ethyl2-[(7-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(2-ethoxy-2-oxoethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(2-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{(7-[4-(aminosulfonyl)benzyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-{[7-(4-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(cyclohexylmethyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[1,3-dimethyl-2,6-dioxo-7-(1-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[1,3-dimethyl-2,6-dioxo-7-(2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-[(1,7-dihexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-[(3-methyl-2,6-dioxo-1,7-dipentyl-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanamide;2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanamide;7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione;ethyl2-{8-[(3-bromobenzyl)thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}butanoate;and ethyl2-[(7-isobutyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate.

In some embodiments compounds are: ethyl2-[(7-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanamide;7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione;and ethyl2-{8-[(3-bromobenzyl)thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}butanoate.

In some embodiments compounds are: ethyl2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;and ethyl2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate.

The acid addition salt form of a compound of formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, a hydrohalicsuch as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric andthe like; or an organic acid, such as, for example, acetic,trifluoroacetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic,succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like.

The compounds of formula I containing acidic protons may be convertedinto their therapeutically active, non-toxic base addition salt forms,e.g. metal or amine salts, by treatment with appropriate organic andinorganic bases. Appropriate base salt forms include, for example,ammonium salts, alkali and earth alkaline metal salts, e.g. lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e.g. N-methyl-D-glucamine, hydrabamine salts, and saltswith amino acids such as, for example, arginine, lysine and the like.

Conversely said salt forms can be converted into the free forms bytreatment with an appropriate base or acid.

Compounds of the formula I and their salts can be in the form of asolvate, which is included within the scope of the present invention.Such solvates include for example hydrates, alcoholates and the like.

Many of the compounds of formula I and some of their intermediates haveat least one stereogenic center in their structure. This stereogeniccenter may be present in a R or a S configuration, said R and S notationis used in correspondence with the rules described in Pure Appl. Chem.,45 (1976) 11-30.

The invention also relates to all stereoisomeric forms such asenantiomeric and diastereoisomeric forms of the compounds of formula Ior mixtures thereof (including all possible mixtures of stereoisomers).

With respect to the present invention reference to a compound orcompounds is intended to encompass that compound in each of its possibleisomeric forms and mixtures thereof, unless the particular isomeric formis referred to specifically. Compounds according to the presentinvention may exist in different polymorphic forms. Although notexplicitly indicated in the above formula, such forms are intended to beincluded within the scope of the present invention.

xiii) U.S. Pat. No. 7,465,549

In some embodiments, the compound includes optionally substitutedN-alkylated 2-oxo-pyrrolidine derivatives. In some embodiments, thosecompounds are alkyl amides derivatives substituted on the positions 4and/or 5 of the pyrrolidone ring. Examples of optionally substitutedN-alkylated 2-oxo-pyrrolidine derivatives include, but are not limitedto, compounds such as(2S)-2-[(4S)-4-(2,2-difluorovinyl)-2-oxopyrrolidinyl]butanamide,(2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butanamide,(2S)-2-[(4S)-2-oxo-4-propylpyrrolidinyl]butanamide, and(2S)-2-[4-(3-azidophenyl)-2-oxopyrrolidin-1-yl]butanamide.

In some embodiments, the compounds further include optionallysubstituted N-alkylated 2-oxo-piperidinyl derivatives. In someembodiments, those compounds are alkyl amides derivatives substituted onthe position 4 and/or 5 and/or 6 of the 2-oxo-piperidinyl ring. Examplesof optionally substituted N-alkylated 2-oxo-pyrrolidine derivativesinclude, but are not limited to, compounds such as those referred to ininternational patent application PCT/EP02/05503 such as(2S)-2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,(2S)-2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-5-phenyl-1-piperidinyl]butanamide,(2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide, and(2S)-2-[4-(2-fluoro-2-methylpropyl)-2-oxo-1-pyrrolidinyl]butanamide.

In some embodiments, the compounds include any acetam compound offormula I, in racemic or isomeric form, or a pharmaceutically acceptablesalt thereof,

wherein

R represents hydrogen or hydroxy;

R1 and R2 represent independently hydrogen or an alkyl group of 1-4carbon atoms; and

R3 and R4 represent independently hydrogen, an alkyl group of 1-4 carbonatoms or —(CH2)n-NR5R6 wherein n is 1, 2 or 3 and R5 and R6 representindependently hydrogen or an alkyl group of 1-4 carbon atoms.

An example of such an acetam compound includes, but is not limited to, acompound of formula I wherein R, R1, R2, R3 and R4 are hydrogen,2-oxo-pyrrolidineacetamide, known by the generic name piracetam asdescribed in UK Patents Nos. 1,039,113 and 1,309,692.

In some embodiments, the compounds also include optionally substitutedN-alkylated 2-oxo-azepanyl derivatives. Preferably, those compounds arealkyl amides derivatives substituted on the positions 4 and/or 5 and/or6 and/or 7 of the 2-oxo-azepanyl ring. Examples of optionallysubstituted N-alkylated 2-oxo-azepanyl derivatives include, but are notlimited to, compounds such as those referred to in international patentapplication PCT/EP02/05503 such as2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide.

xiv) U.S. Patent Application Publication No. 2006258704

This invention provides novel compounds of the formula I

wherein

n represents 0 or 1 whereby R<1> is not existent when n=0 and R<1> isexistent

when n=1;

A<1> represents an oxygen or a sulfur atom;

X is —CONR<7>R<8>, —COOR<9>, —CO—R<10> or CN; R<1> when existent, R<2>,R<3>, R<4> and R<5> are the same or different and each is independentlyhydrogen, halogen, hydroxy, thiol, amino, nitro, nitrooxy, cyano, azido,carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl,ester, ether, aryl, heterocycle, or an oxy derivative, thio derivative,amino derivative, acyl derivative, sulfonyl derivative or sulfinylderivative, provided that at least one of the substituents R chosen fromR<1> when existent,

R<2>, R<3>, R<4> or R<5> is not hydrogen;

R<6> is hydrogen, alkyl, aryl or —CH2-R<6a> wherein R<6a> is aryl,heterocycle, halogen, hydroxy, amino, nitro or cyano;

R<7>, R<8> and R<9> are the same or different and each is independentlyhydrogen, hydroxy, alkyl, aryl, heterocycle or an oxy derivative; and

R<10> is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle ora thio derivative;

their pharmaceutically acceptable salts, geometrical Isomers (includingcis and trans, Z and E isomers), enantiomers, diastereoisomers andmixtures thereof (including all possible mixtures of stereoisomers).

In the above formula, at least one substituent R<1> to R<5> is differentfrom hydrogen. Some non-substituted compounds are referred to in U.S.Pat. Nos. 5,468,733 and 5,516,759. U.S. Pat. No. 5,468,733 disclosesnon-ring substituted 2-oxo-1-pyrrolidinyl and 2-oxo-1-piperidinylderivatives as inhibitors of the oncogene Ras protein. In particular,these compounds block the ability of Ras to transform normal cells tocancer cells, and therefore can be included in several chemotherapeuticcompositions for treating cancer.

U.S. Pat. No. 5,516,759 discloses non-ring substituted2-oxo-1-pyrrolidinyl, 2-oxo-1-piperidinyl and azepanyl derivativespresent at the N-terminus of dodecapeptides possessing LHRH (luteinizinghormone-releasing hormone) antagonistic activity. Such LHRH antagonistsare useful in the treatment of a variety of conditions in whichsuppression of sex steroids plays a key role including contraception,delay of puberty, treatment of benign prostatic hyperplasia a. o.

In the definitions set forth below, unless otherwise stated, R<11> andR<12> are the same or different and each is independently amido, alkyl,alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl, heterocycle or anoxy derivative, thio derivative, acyl derivative, amino derivative,sulfonyl derivative, or sulfinyl derivative, each optionally substitutedwith any suitable group, including, but not limited to, one or moremoieties selected from lower alkyl or other groups as described below assubstituents for alkyl.

The term “oxy derivative”, as used herein, is defined as including—O—R<11> groups wherein R<11> is as defined above except for “oxyderivative”. Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy,acyloxy, oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy,arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy or heterocyclooxysuch as pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy,2-naphthyloxy, 2-pyridyloxy, methylenedioxy, carbonate.

The term “thio derivative”, as used herein, is defined as including—S—R<11> groups wherein R<11> is as defined above except for “thioderivative”. Non-limiting examples are alkylthio, alkenylthio,alkynylthio and arylthio.

The term “amino derivative”, as used herein, is defined as including—NHR<11> or —NR<11>R<12> groups wherein R<11> and R<12> are as definedabove. Non-limiting examples are mono- or di-alkyl-, alkenyl-, alkynyl-and arylamino or mixed amino.

The term “acyl derivative”, as used herein, represents a radical derivedfrom carboxylic acid and thus is defined as including groups of theformula R<11>-CO—, wherein R<11> is as defined above and may also behydrogen. Preferred are acyl derivatives of formula —COR<11> whereinR<11> is selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12alkenyl, heterocyle and aryl. Non-limiting examples are formyl, acetyl,propionyl, isobutyryl, valeryl, lauroyl, heptanedioyl,cyclohexanecarbonyl, crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl,furoyl, nicotinoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl,oxamoyl.

The term “sulfonyl derivative”, as used herein, is defined as includinga group of the formula —SO—R<11>, wherein R<11> is as defined aboveexcept for “sulfonyl derivative”. Non-limiting examples arealkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.

The term “sulfinyl derivative”, as used herein, is defined as includinga group of the formula —SO—R<11>, wherein R<11> is as defined aboveexcept for “sulfinyl derivative”. Non-limiting examples arealkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl.

The term “alkyl”, as used herein, is defined as including saturated,monovalent hydrocarbon radicals having straight, branched or cyclicmoieties or combinations thereof and generally containing 1-20 carbonatoms, most often 1 to 12 carbon atoms, preferably 1-7 carbon atoms fornon-cyclic alkyl and 3-7 carbon atoms for cycloalkyl (in these twopreferred cases, unless otherwise specified, “lower alkyl”), eachoptionally substituted by, preferably 1 to 5, substituents independentlyselected from the group consisting of halogen, hydroxy, thiol, amino,nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulfinylderivative, alkylamino, carboxy, ester, ether, amido, azido, cycloalkyl,sulfonic acid, sulfonamide, thio derivative, alkylthio, oxyester,oxyamido, heterocycle, vinyl, alkoxy (preferably C1-5), aryloxy(preferably C6-10) and aryl(preferably C6-10).

In some embodiments are alkyl groups containing 1 to 7 carbon atoms,each optionally substituted by one or more substituents selected fromhydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio,cyclopropyl, acyl and phenyl. Most preferred are C1-4 alkyl and C3-7cycloalkyl, each optionally substituted by one or more hydroxy, halogen,lower alkyl or/and azido.

In some embodiments are alkyl groups are hydroxymethyl, propyl, butyl,2,2,2-trifluoroethyl, 2-bromo-2,2-difluoroethyl,2-chloro-2,2-difluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl,iodomethyl, azidomethyl, 2,2-difluoropropyl, 2-iodo-2,2-difluoroethyl.

The term “lower alkyl”, as used herein, and unless otherwise specified,refers to C1 to C7 saturated straight, branched or cyclic hydrocarbon.Non limiting examples are methyl, ethyl, propyl, isopropyl, butyl,tertiobutyl, pentyl, cyclopropyl, cyclopentyl, isopentyl, neopentyl,hexyl, isohexyl, cyclohexyl, 3-methypentyl, 2,2-dimethylbutyl,optionally substituted with any suitable group, including but notlimited to one or more moieties selected from groups as described abovefor the alkyl groups. Preferably, lower alkyl is methyl.

The term “alkenyl”, as used herein, is defined as including bothbranched and unbranched, unsaturated hydrocarbon radicals having atleast one double bond, and being optionally substituted by at least onesubstituent selected from the group consisting of halogen, hydroxy,thiol, amino, thiocyanato, azido, alkylthio, cycloalkyl, acyl, nitro,cyano, aryl and heterocycle.

In some embodiments are alkenyl groups are C2-C12 alkenyls, especiallyC2-6alkenyls, such as ethenyl (=vinyl), 1-methyl-1-ethenyl,2,2-dimethyl-1-ethenyl, 1-propenyl, 2-propenyl (=allyl), 1-butenyl,2-butenyl, 3-butenyl, 4-pentenyl, 1-methyl-4-pentenyl,3-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl and the like, optionally beingsubstituted by one or more substituents selected from halogen, cyano,thiocyanato, azido, alkylthio, cycloalkyl, phenyl and acyl. Mostpreferred is vinyl, optionally substituted by one or more halogen or/andlower alkyl, and especially 2,2-difluorovinyl, 2,2-dibromovinyl and2,2-dichlorovinyl.

The term “alkynyl” as used herein, is defined as including a monovalentbranched or unbranched hydrocarbon radical containing at least onecarbon-carbon triple bond, for example ethynyl, 2-propynyl (=propargyl),and the like, and being optionally substituted by at least onesubstituent selected from the group consisting of halogen, hydroxy,thiol, amino, nitro, cyano, aryl, heterocycle, thiocyanato, azido,alkylthio, alkyl and acyl.

In some embodiments are alkynyl groups are C2-12 alkynyl, especiallyC2-6 alkynyl, optionally being substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, acyl, arylsuch as phenyl and alkyl, preferably cycloalkyl.

In some embodiments are ethynyl, propynyl and butynyl, optionallysubstituted by lower alkyl or/and halogen, and especially 1-propynyl,cyclopropylethynyl, 3-methyl-1-butynyl and 3,3,3-trifluoro-1-propynyl.

When present as bridging groups, alkyl, alkenyl and alkynyl representstraight- or branched chains, C1-12, preferably C1-4-alkylene or C2-12-,preferably C2-4-alkenylene or -alkynylene moieties respectively.

Groups where branched derivatives are conventionally qualified byprefixes such as “n”, “sec”, “iso” and the like (e.g. “n-propyl”,“sec-butyl”) are in the n-form unless otherwise stated.

The term “aryl”, as used herein, is defined as including an organicradical derived from an aromatic hydrocarbon consisting of at least onering, most often 1 to 3 rings and generally containing 6-30 carbon atomsby removal of one hydrogen, such as phenyl and naphthyl, each optionallysubstituted by one or more substituents independently selected fromhalogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl,sulfinyl, alkylamino, carboxy, ester, ether, amido, azido, sulfonicacid, sulfonamide, alkylsulfonyl, alkylsulfinyl, C1-6-alkylthio,oxyester, oxyamido, aryl, C1-6-alkoxy, C6-10-aryloxy, C1-6-alkyl,C1-6-haloalkyl. Aryl radicals are preferably monocyclic or bicycliccontaining 6-10 carbon atoms. Preferred aryl groups are phenyl andnaphthyl each optionally substituted by one or more substituentsindependently selected from halogen, nitro, amino, azido, C1-6-alkoxy,C1-6-alkyl, C1-6-haloalkyl, sulfonyl and phenyl. In some embodiments thearyl is phenyl, optionally substituted by one or more halogen, loweralkyl, azido or nitro, such as 3-chlorophenyl and 3-azidophenyl.

The term “halogen”, as used herein, includes an atom of C1, Br, F, I.

The term “hydroxy”, as used herein, represents a group of the formula—OH.

The term “thiol”, as used herein, represents a group of the formula —SH.

The term “cyano”, as used herein, represents a group of the formula —CN.

The term “nitro”, as used herein, represents a group of the formula—NO2.

The term “nitrooxy”, as used herein, represents a group of the formula—ONO2.

The term “amino”, as used herein, represents a group of the formula—NH2.

The term “azido”, as used herein, represents a group of the formula —N3.

The term “carboxy”, as used herein, represents a group of the formula—COOH.

The term “sulfonic acid”, as used herein, represents a group of theformula —SO3H.

The term “sulfonamide”, as used herein, represents a group of theformula —SO2NH2.

The term “ester”, as used herein, is defined as including a group offormula —COO—R<11> wherein R<11> is as defined above except oxyderivative, thio derivative or amino derivative. Preferred are esters offormula —COOR<11> wherein R<11> is selected from C1-12 alkyl, C2-12alkenyl, C2-12 alkynyl and aryl. Most preferred are esters where R<11>is a lower alkyl, especially methyl.

The term “ether” is defined as including a group selected fromC1-50-straight or branched alkyl, or C2-50-straight or branched alkenylor alkynyl groups or a combination of the same, interrupted by one ormore oxygen atoms.

The term “amido” is defined as including a group of formula —CONH2 or—CONHR<11> or —CONR<11>R<12> wherein R<11>r and R<12> are as definedabove.

The term “heterocycle”, as used herein, is defined as including anaromatic or non aromatic cyclic alkyl, alkenyl, or alkynyl moiety asdefined above, having at least one O, S and/or N atom interrupting thecarbocyclic ring structure and optionally, one of the carbon of thecarbocyclic ring structure may be replaced by a carbonyl, and optionallybeing substituted with any suitable group, including but not limited toone or more moieties selected from lower alkyl, or other groups asdescribed above for the alkyl groups. Non-limiting examples ofheterocycles are pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl,triazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl,quinolizinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl,indolyl, indolizinyl, purinyl, isoindolyl, carbazolyl, thiazolyl,1,2,4-thiadiazolyl, thiomorpholinyl, thieno(2,3-b)furanyl, furopyranyl,benzofuranyl, benzoxepinyl, isooxazolyl, oxazolyl, thianthrenyl,benzothiazolyl, or benzoxazolyl, cinnolinyl, phthalazinyl, quinoxalinyl,1-oxidopyridyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenothiazinyl, furazanyl, benzodioxolyl, isochromanyl,indolinyl, xanthenyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl,5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,pyrrolopyrimidinyl, pyrazolopyrimidinyl, tetrahydrofuranyl,tetrahydropyranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl,morpholino, morpholinyl, 1-oxaspiro(4.5)dec-2-yl, pyrrolidinyl,2-oxo-pyrrolidinyl, sugar moieties (i.e. glucose, pentose, hexose,ribose, fructose, which may also be substituted) optionally substitutedby alkyl or as described above for the alkyl groups. The term“heterocycle” also includes bicyclic, tricyclic and tetracyclic, spirogroups in which any of the above heterocyclic rings is fused to one ortwo rings independently selected from an aryl ring, a cyclohexane ring,a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or anothermonocyclic heterocyclic ring or where a monocyclic heterocyclic group isbridged by an alkylene group, such as quinuclidinyl,7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2. 1)heptanyl,8-azabicyclo(3.2.1)octanyl.

The heterocycle may be selected from triazolyl, tetrazolyl,pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl,furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyland piperazinyl, each optionally substituted by one or more substituentsselected from halogen, alkyl, substituted alkyl, alkoxy, nitro, amino,acyl and phenyl. In some embodiments the heterocycle is selected fromtetrazolyl, pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl andthienyl, each optionally substituted by one or more substituentsselected from halogen, alkyl, halogen substituted alkyl, acyl, alkoxy,nitro, amino and phenyl, and especially from 2- and 3-thienyl,optionally substituted by one or more halogen, acyl such as formyl,cyano and/or lower alkyl, such as methyl.

In the above definitions it is to be understood that when a substituentsuch as R<1>, R<2>, R<3>, R<4>, R<5>, R<7>, R<8>, R<9>, R<10> isattached to the rest of the molecule via a heteroatom or a carbonyl, astraight- or branched chain, C1-12-, preferably C1-4-alkylene or C2-12,preferably C2-4-alkenylene or -alkynylene bridge may optionally beinterposed between the heteroatom or the carbonyl and the point ofattachment to the rest of the molecule.

The acid addition salt form of a compound of formula (I) that occurs inits free form as a base can be obtained by treating said free base formwith an appropriate acid such as an inorganic acid, for example, ahydrohalic such as hydrochloric or hydrobromic, sulfuric, nitric,phosphoric and the like; or an organic acid, such as, for example,acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic,maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like.

The compounds of formula (I) containing acidic protons may be convertedinto their therapeutically active, non-toxic base addition salt form,e.g. metal or amine salts, by treatment with appropriate organic andinorganic bases. Appropriate base salt forms include, for example,ammonium salts, alkali and earth alkaline metal salts, e.g. lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e.g. N-methyl-D-glucamine, hydrabamine salts, and saltswith amino acids such as, for example, arginine, lysine and the like.

Conversely said salt forms can be converted into the free forms bytreatment with an appropriate base or acid.

Compounds of the formula I and their salts can be in the form of asolvate, which is included within the scope of the present invention.Such solvates include for example hydrates, alcoholates and the like.

Many of the compounds of formula I and some of their intermediates haveat least one stereogenic center in their structure. This stereogeniccenter may be present in a R or a S configuration, said R and S notationis used in correspondence with the rules described in Pure Appl. Chem.(1976), 45, 11-30.

The invention also relates to all stereoisomeric forms such asenantiomeric and diastereoisomeric forms of the compounds of formula Ior mixtures thereof (including all possible mixtures of stereoisomers).

Furthermore, certain compounds of formula I which contain alkenyl groupsmay exist as Z (zusammen) or E (entgegen) isomers. In each instance, theinvention includes both mixture and separate individual isomers.

Multiple substituents on the piperidinyl or the azepanyl ring can alsostand in either cis or trans relationship to each other with respect tothe plane of the piperidinyl or the azepanyl ring.

Some of the compounds of formula I may also exist in tautomeric forms.Such forms although not explicitly indicated in the above formula areintended to be included within the scope of the present invention.

With respect to the present invention reference to a compound orcompounds is intended to encompass that compound in each of its possibleisomeric forms and mixtures thereof unless the particular isomeric formis referred to specifically. The invention also includes within itsscope prodrug forms of the compounds of formula I and Its varioussub-scopes and sub-groups.

The term “prodrug” as used herein includes compound forms which arerapidly transformed in vivo to the parent compound according to theinvention, for example, by hydrolysis in blood. Prodrugs are compoundsbearing groups which are modified by biotransformation prior toexhibiting their pharmacological action. Such groups include moietieswhich are readily oxidised, cyclised or cleaved, which compound afterbiotransformation remains or becomes pharmacologically active. Forexample, metabolically cleavable groups form a class of groups wellknown to practitioners of the art. They include, but are not limited tosuch groups as alkanoyl (i.e. acetyl, propionyl, butyryl, and the like),unsubstituted and substituted carbocyclic aroyl (such as benzoyl,substituted benzoyl and 1- and 2-naphthoyl), alkoxycarbonyl (such asethoxycarbonyl), trialkylsilyl (such as trimethyl- and triethylsilyl),monoesters formed with dicarboxylic acids (such as succinyl), phosphate,sulfate, sulfonate, sulfonyl, sulfinyl and the like. The compoundsbearing the biotransformable groups have the advantage that they mayexhibit improved bioavailability as a result of enhanced solubilityand/or rate of absorption conferred upon the parent compound by virtueof the presence of the biotransformable group. T. Higuchi and V. Stella,“Pro-drugs as Novel Delivery System”, Vol. 14 of the A.C.S. SymposiumSeries; “Bioreversible Carriers in Drug Design”, ed. Edward B. Roche,American Pharmaceutical Association and Pergamon Press, 1987.

The term “R substituent” refers to R<1>, R<2>, R<3>, R<4> or R<5>,independently.

According to one embodiment, the present invention relates to a compoundof formula I as defined above wherein n represents 0. The compound is a6-ring structure (2-thioxo- or 2-oxo-piperidinyl derivative) whereinR<1> is not existent since n=0, and is depicted by the formula (I-A).

According to a following embodiment, the present invention relates to acompound of formula I according to the invention as defined abovewherein n represents 1. The compound is a 7-ring structure (2-thioxo- or2-oxo-azepanyl derivative) wherein R<1> is existent since n=1 anddepicted by the formula (I-B).

According to one embodiment, the invention relates to said compound asdefined above wherein n=0, R<3> and/or R<4> are different from hydrogenand R<2> and R<5> represent hydrogen.

According to another embodiment, the invention relates to said compoundas defined above wherein n=1, R<2>, R<3> and/or R<4> are different fromhydrogen and wherein R<1> and R<5> represent hydrogen.

According to another embodiment, the invention relates to said compoundas defined above wherein only one R substituent chosen from R<3> or R<4>when n=0 or from R<2>, R<3> or R<4> when n=1, is different from hydrogenand the remaining R substituent(s) is/are hydrogen. We hereby refer to amono-substituted 2-thioxo- or 2-oxo-piperidinyl or 2-thioxo- or2-oxo-azepanyl derivatives. According to another embodiment, the presentinvention relates to compounds of formula I according to the inventionas defined above wherein A<1> represents an oxygen atom. We hereby referto 2-oxo-piperidinyl or 2-oxo-azepanyl derivatives.

According to another embodiment, the present invention relates tocompounds of formula I according to the invention as defined abovewherein X is CONR<7>R<8>, especially CONH2. We hereby refer to amidoderivatives of 2-oxo(or thioxo)-piperidinyl or 2-oxo(orthioxo)-azepanyl.

According to another embodiment, the present invention relates tocompounds of formula I according to the invention as defined abovewherein R<6> represents hydrogen, C1-4 alkyl, or a CH2-R<6a> groupwherein R<6a> represents a heterocycle. Most preferably R<6> is a C1-4alkyl, especially ethyl. When R<6> is ethyl we refer to 2-(2-oxo(orthioxo)-1-piperidinyl)butanamide or 2-(2-oxo(orthioxo)-1-azepanyl)butanamide derivatives.

According to another embodiment, the present invention relates tocompounds of formula I according to the invention as defined abovewherein the carbon atom to which R<6> is attached is of the Sconfiguration. In case where R<6> is ethyl, A is oxygen and X is CONR<7>R<8>, we refer then to (2S)-2-(2-oxo-1-piperidinyl)butanamide or(2S)-2-(2-oxo-1-azepanyl)butanamide derivatives.

According to one embodiment, the present invention relates to a compoundas defined above wherein R<2> when n=1, R<3> and R<4> are the same ordifferent and each is independently hydrogen, halogen, nitro, nitrooxy,cyano, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl,alkynyl, ester, ether, aryl, heterocycle, acyl derivative, sulfonylderivative or sulfinyl derivative:

R<1> when existent, R<2> when n=0 and R<5> are hydrogen;

R<6> is hydrogen, alkyl, aryl or —CH2-R<6a> wherein R<6a> is aryl,heterocycle, halogen, hydroxy, amino, nitro or cyano;

provided that, when R<6> is hydrogen, X is —CONR<7>R<8> and that thecompound is neither methyl(2R)-2-[(6R)-6-methyl-2-oxoazepanyl]-3-phenylpropanoate nor methyl(2S)-2-[(4R)-4-methyl-2-oxoazepanyl]-3-phenylpropanoate.

According to this embodiment, the compound is generally such that whenR<6> is benzyl, X is —COOCH3 and n=1, R<2> is different from methyl whenR<3> and R<4> are both hydrogen and R<4> is different from methyl whenR<2> and R<3> are both hydrogen.

According to another embodiment, the present invention relates to acompound as defined above wherein R<2> when n=1, R<3> and R<4> are thesame or different and each is independently hydrogen; cyano; carboxy;amido;

C1-12 alkyl, each optionally substituted by one or more substituentsselected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido,alkyltio, cycloalkyl, acyl, aryl and heterocycle;

C2-12 alkenyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryland acyl;

C2-12 alkynyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryland acyl; acyl derivative of formula —CO—R<11>, wherein R<11> isselected from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, heterocycle andaryl;

ester of formula —CO—O—R<11> wherein R<11> is selected from C1-12 alkyl,C2-12 alkenyl, C2-12 alkynyl and aryl;

heterocycle selected from triazolyl, tetrazolyl, pyrrolidinyl, pyridyl,1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl,pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl and piperazinyl,each optionally substituted by one or more substituents selected fromhalogen, alkyl, substituted alkyl, alkoxy, nitro, amino, acyl andphenyl;

aryl, each optionally substituted by one or more substituents selectedfrom C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, amino,azido, sulfonyl, aryl and nitro.

According to another embodiment, the present invention relates to acompound as defined above, wherein R<2> when n=1, R<3> and R<4> are thesame or different and each is independently hydrogen;

C1-7 alkyl, each optionally substituted by one or more substituentsselected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido,alkyltio, cyclopropyl, acyl and phenyl;

C2-6 alkenyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl,phenyl and acyl:

C2-6 alkynyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl,phenyl and acyl: heterocycle selected from tetrazolyl, pyrrolidinyl,pyridyl, furyl, pyrrolyl, thiazolyl and thienyl, each optionallysubstituted by one or more substituents selected from halogen, alkyl,halogen substituted alkyl, acyl, alkoxy, nitro, amino and phenyl;

phenyl, each optionally substituted by one or more substituents selectedfrom C1-6 alkyl, halogen substituted alkyl, halogen, alkoxy, amino,azido, sulfonyl, phenyl and nitro.

According to another embodiment, the present invention relates to acompound as defined above wherein at least one of the R substituentschosen from the group R<2>, R<3> and R<4> when n=1 or from the groupR<3> and R<4> when n=0, represents independently C1-4-alkyl orC3-7-cycloalkyl, optionally substituted by one or more halogen, hydroxy,lower alkyl and/or azido.

According to another embodiment, the present invention relates to acompound as defined above wherein at least one of the R substituentschosen from the group R<2>, R<3> and R<4> when n=1 or from the groupR<3> and R<4> when n=0, represents independently vinyl, optionallysubstituted by one or more halogen or/and lower alkyl.

According to another embodiment, the present invention relates to acompound as defined above wherein at least one of the R substituentschosen from the group R<2>, R<3> and R<4> when n=1 or from the group R3and R<4> when n=0, represents independently ethynyl, propynyl orbutynyl, optionally substituted by one or more halogen and/or loweralkyl.

According to another embodiment, the present invention relates to acompound as defined above wherein at least one of the R substituentschosen from the group R<2>, R<3> and R<4> when n=1 or from the groupR<3> and R<4> when n=0, represents independently phenyl, optionallysubstituted by one or more halogen, lower alkyl, azido and/or nitro.

According to another embodiment, the present invention relates to acompound as defined above wherein at least one of the R substituentschosen from the group R<2>, R<3> and R<4> when n=1 or from the groupR<3> and R<4> when n=0, represents independently 2- or 3-thienyl,optionally substituted by one or more halogen, acyl, cyano or/and loweralkyl.

According to a particular embodiment, the present invention relates to acompound as defined above wherein at least one of the R substituentschosen from the group R<3>, R<4> and R<2> when n=1 or from the groupR<3> and R<4> when n=0, is hydroxymethyl, propyl, butyl,3,3,3-trifluoropropyl, 2,2,2-trifluoroethyl, cyclopropylmethyl,iodomethyl, azidomethyl, 2-thienyl, 3-thienyl, phenyl, 3-chlorophenyl,3-azidophenyl, 2,2-difluorovinyl, 2,2-dibromovinyl, 2,2-dichlorovinyl,2-ethynyl, 5-methyl-2-thienyl, 5-formyl-2-ethynyl, 5-cyano-2-thienyl,3-bromo-2-thienyl, 4-methyl-2-thienyl, 3,3,3-trifluoro-1-propynyl,1-propynyl, cyclopropylethynyl, 3-methyl-1-butynyl, 1-butynyl,2,2-difluoropropyl, 2-chloro-2,2-difluoroethyl,2-bromo-2,2-difluoroethyl and 2-iodo-2,2-difluoroethyl.

According to yet another embodiment, the present invention relates to acompound as defined above wherein R<1>, R<2>, R<4> and R<5> arehydrogen.

According to another embodiment, the present invention relates to acompound as defined above wherein R<1>, R<2>, R<3> and R<5> arehydrogen.

According to another embodiment, the present invention relates to acompound as defined above wherein n=1 and R<1>, R<3>, R<4> and R<5> arehydrogen.

In all the above-mentioned scopes when the carbon atom to which R<6> isattached is asymmetric it may be in the “S”-configuration.

Representative compounds of this invention as defined above are selectedfrom the group consisting of2-[5-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-5-propyl-1-piperidinyl)butanamide,2-12-oxo-5-(3,3,3-trifluoropropyl)-1-piperidinyl]butanamide,2-[5-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-5-phenyl-1-piperidinyl)butanamide,2-[2-oxo-5-(2-thienyl)-1-piperidinyl]butanamide,2-[2-oxo-5-(3-thienyl)-1-piperidinyl]butanamide,2-[5-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide,2-(5-ethynyl-2-oxo-1-piperidinyl)butanamide,2-[5-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[2-oxo-5-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl]butanamide,2-[2-oxo-5-(1-propynyl)-1-piperidinyl]butanamide,2-[5-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(1-butynyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2,2-difluoropropyl)-2-oxo 1-piperidinyl]butanamide,2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-4-propyl-1-piperidinyl)butanamide,2-[2-oxo-4-(3,3,3-trifluoroproyl)-1-piperidinyl]butanamide,2-14-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-4-phenyl-1-piperidinyl)butanamide,2-12-oxo-4-(2-thienyl)-1-piperidinyl]butanamide,2-[2-oxo-4-(3-thienyl)-1-piperidinyl]butanamide,2-[4-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide,2-(4-ethynyl-2-oxo-1-piperidinyl)butanamide,2-[4-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2[4-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[2-oxo-4-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl]butanamide,2-[2-oxo-4-(1-propynyl)-1-piperidinyl]butanamide,2-[4-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(1-butynyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-14-(2-bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2,2-trifluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-5-propyl-1-azepanyl)butanamide,2-[2-oxo-5-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,2-(5-(cyclopropylmethyl)-2-oxo-1-azepanyl)butanamide,2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide,2-[5-(azidomethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-5-phenyl-1-azepanyl)butanamide,2-[2-oxo-5-(2-thienyl)-1-azepanyl]butanamide,2[2-oxo-5-(3-thienyl)-1-azepanyl]butanamide,2-[5-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,2-[5-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,2[5-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,2-(5-ethynyl-2-oxo-1-azepanyl)butanamide,2-[5-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[5-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[5-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[5-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[5-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[2-oxo-5-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,2-[2-oxo-5-(1-propynyl)-1-azepanyl]butanamide,2-[5-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,2-[5-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[5-(1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[6-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-6-propyl-1-azepanyl)butanamide,2-[2-oxo-6-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,2-[6-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,2-[6-(iodomethyl)-2-oxo-1-azepanyl]butanamide,2-16-(azidomethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-6-phenyl-1-azepanyl)butanamide,2-[2-oxo-6-(2-thienyl)-1-azepanyl]butanamide,2[2-oxo-6-(3-thienyl)-1-azepanyl]butanamide,2-[6-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,2-[6-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,2-(6-ethynyl-2-oxo-1-azepanyl)butanamide,2-[6-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[6-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2[6-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[6-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[6-(4-methyl-2-thienyl]-2-oxo-1-azepanyl]butanamide,2-[2-oxo-6-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,2[2-oxo-6-(1-propynyl)-1-azepanyl]butanamide,2[6-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,2[6-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[6-(1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[4-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-4-propyl-1-azepanyl)butanamide,2-[2-oxo-4-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,2-14-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,2-[4-(iodomethyl)-2-oxo-1-azepanyl]butanamide,2-[4-(azidomethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-4-phenyl-1-azepanyl)butanamide,2-[2-oxo-4-(2-thienyl)-1-azepanyl]butanamide,2[2-oxo-4-(3-thienyl)-1-azepanyl]butanamide,2-f4-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,2-[4-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,2-(4-ethynyl-2-oxo-1-azepanyl)butanamide,2-[4-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[4-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[<4>-(5-cyano-<2>-thienyl)-2-oxo-1-azepanyl]butanamide,2-[4-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[4-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2[2-oxo-4-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,2[2-oxo-4-(1-propynyl)-1-azepanyl]butanamide,2-[4-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,2-[4-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[4-(1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2-chloro-2,2-difluoroethyl]-2-oxo-1-azepanyl]butanamide,2-[4-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide.

Results have been obtained with the following compounds:

-   (2S)-2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,-   (2S)-2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-(2-oxo-5-phenyl-1-piperidinyl]butanamide,-   (2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide.

xv) International Patent Application Publication No. WO2008/132139

In some embodiments, the compounds are of formula (I) as follows:

wherein

Y is O or S. In some embodiments Y is O. R1 is hydrogen or C-|.g alkyl;

R2 is hydrogen;

R3 is —CONR5R6, —COR7, an imidazolyl, an imidazopyridinyl, animidazopyridazinyl; R5, R6 are the same or different and areindependently selected from hydrogen and C-|_6 alkyl; R7 is C<;|_6alkyl;

A is a monocyclic or bicyclic heterocyclic moiety selected from thegroup consisting of imidazolidin-1-yl, 1,3-oxazolidin-3-yl,2,5-dihydro-1H-pyrrol-1-yl, 1,3-thiazol-3(2H)-yl, 1,3-thiazolidin-3-yl,piperidin-1-yl, azepan-1-yl, 5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl,hexahydro-4H-thieno[3,2-b]pyrrol-4-yl,2,3-dihydro-1H-thieno[3,4-b]pyrrol-1-yl, 1,3-benzothiazol-3(2H)-yl,1,3-benzoxazol-3(2H)-yl, pyrazolo[1,5-a]pyridin-1 (2H)-yl,3,4-dihydroisoquinolin-2(1 H)-yl, 3,4-dihydroquinolin-1 (2H)-yl,1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl,1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl; R4 is either R̂a or R̂b dependingon whether A being is a monocyclic or a bicyclic heterocycle:

where A is a monocyclic heterocyclic moiety, R̂ is R̂a which is selectedfrom the group consisting of hydrogen; C-|.g alkyl optionallysubstituted by a substituent selected from halogen, C-1.4 alkoxy, C-1.4alkylthio, azido, nitrooxy or an aryl; C2-6 alkenyl optionallysubstituted by halogen; C2-6 alkynyl optionally substituted by halogen;azido; alkoxycarbonylamino; arylsulfonyloxy; a substituted orunsubstituted aryl; or a 3-8 membered substituted or unsubstitutedheterocycle; where A is a bicyclic heterocyclic moiety R̂ is R̂ which isselected from the group comprising or consisting of hydrogen; nitro;cyano; halogen; heterocycle; amino; aryl; C-|.g alkyl optionallysubstituted by at least one halogen; or C-|.g alkoxy optionallysubstituted by at least one halogen;

In some embodiments the compounds are as follows:

For compounds where A=Y is selected from a 2-oxo-piperidin-1-yl, a2-oxo-azepan-1-yl, a 2-oxo-1,3-benzothiazol-3(2H)-yl or a2-oxo-1,3-benzoxazol-3(2H)-yl, R3 must be selected from an imidazolyl,an imidazopyridinyl or an imidazopyridazinyl.

For compounds where A=Y is a 5-oxoimidazolidin-1-yl, R̂ and R̂ arehydrogen, R3 is —CONR5R6, R5 and R6 are as above defined, then R̂a maynot be an alkyl, aralkyl or substituted aralkyl.

Where A=Y is either of a 2-oxo-piperidin-1-yl and a 2-oxo-azepan-1-yl,R̂, R̂ and R̂a are all hydrogen, then R̂ could not be a2-phenylimidazo[1,2-a]pyridin-3-yl.

In a specific embodiment A=Y is selected from the list consisting of:

wherein X is O or S, in a more specific embodiment O; in anotherembodiment, X is S.

The asterisks in the above illustration indicate the attachment sites ofthe substituent R̂a.

In a specific embodiment, when R̂ is —CONR5R6 and R̂ is C-μg alkyl, thecarbon atom to which R-I and R̂ are attached is preferably in the“S”-configuration.

In a specific embodiment R̂ is hydrogen, methyl, ethyl and R̂ is hydrogen.In a specific embodiment R3 is —CONH2.

In a further specific embodiment R̂ is 1 H-imidazol-1-yl, 1H-imidazol-4-yl, 1 H-imidazol-5-yl, imidazo[1,2-a]pyridin-3-yl orimidazo[1,2-b]pyridazin-3-yl. In a specific embodiment R̂a is a C-|.galkyl which may optionally be substituted by a halogen; or a phenyl.

In another specific embodiment R̂b is hydrogen, halogen, nitro, cyano ora C-μg alkyl optionally substituted by a halogen.

In still a further embodiment compounds may be used in the treatment ofthe above mentioned disorders, in particular of epilepsy, having theformula (I-E), as wells as its geometrical isomers, enantiomers,diastereomers and mixtures, or a pharmaceutically acceptable saltthereof,

wherein

X is O or S;

R-I is hydrogen or C-|.g alkyl, in a more specific embodiment hydrogen;

R3 is an imidazolyl, an imidazopyridinyl, an imidazopyridazinyl; R̂b ishydrogen; nitro; cyano; halogen; C-|.g alkyl optionally substituted byhalogen; C-|.g alkoxy optionally substituted by halogen.

A further aspect of the present invention consists in novel compoundshaving the formula (I-A), their geometrical isomers, enantiomers,diastereomers and mixtures, or a pharmaceutically acceptable saltthereof,

wherein

R1 is hydrogen or C-|.g alkyl, preferably hydrogen, methyl or ethyl; ina more specific embodiment R̂ is ethyl.

R3 is —CONH2, an imidazolyl, an imidazopyridinyl, an imidazopyridazinyl,preferably R̂ is —CONH2.

R̂a is either hydrogen or an aryl; with the proviso that2-(5-oxoimidazolidin-1-yl)acetamide is excluded. Preferably R̂a is anaryl, e.g. a phenyl which may be substituted preferably by halogen,nitro, alkoxy, in particular by nitro.

In a particular embodiment, when R̂ is —CONH2 and R̂ is C-|.g alkyl, thecarbon atom to which R1 and R̂ are attached is preferably in the“S”-configuration.

A further aspect of the present invention consists in novel compoundshaving the formula (I-B1 or I-B2), their geometrical isomers,enantiomers, diastereomers and mixtures, or a pharmaceuticallyacceptable salt thereof,

wherein X in formula (I-B2) is either S or O, in a more specificembodiment S; R1 is hydrogen or C-|.g alkyl, preferably hydrogen, methylor ethyl; in a more specific embodiment R̂ is ethyl.

R3 is —CONH2, an imidazolyl, an imidazopyridinyl, an imidazopyridazinyl;preferably R̂ is —CONH2

R̂a is hydrogen; C-|.g alkyl optionally substituted by halogen or C-1.4alkoxy; an aryl; or C2.g alkenyl optionally substituted by halogen.Preferably, R̂a is C-|.g alkyl optionally substituted by halogen or C2-6alkenyl optionally substituted by halogen or an aryl. In a more specificembodiment R̂a is C-|.g alkyl optionally substituted by halogen or aryl.

In a particular embodiment, when R̂ is —CONH2 and R̂ is C-|.g alkyl, thecarbon atom to which R-I and R̂ are attached is preferably in the“S”-configuration.

A further aspect of the present invention consists in novel compoundshaving the formula (I-B3), their geometrical isomers, enantiomers,diastereomers and mixtures, or a pharmaceutically acceptable saltthereof,

wherein

R1 is either hydrogen or C-μg alkyl, preferably hydrogen, methyl orethyl; more preferably R1 is ethyl.

R3 is —CONH2, an imidazolyl, an imidazopyridinyl, an imidazopyridazinyl;

preferably R̂ is —CONH2 R̂a is C-|_5 alkyl optionally substituted byhalogen or C-1.4 alkoxy; an aryl; or C2_g alkenyl optionally substitutedby halogen. Preferably, R̂a is C-|.g alkyl optionally substituted byhalogen or C2_g alkenyl optionally substituted by halogen.

In a particular embodiment, when R̂ is —CONH2 and R̂ is C-|.g alkyl, thecarbon atom to which R-I and R̂ are attached is preferably in the“S”-configuration.

A further aspect of the present invention consists in novel compoundshaving the formula (I-C), their geometrical isomers, enantiomers,diastereomers and mixtures, or a pharmaceutically acceptable saltthereof,

wherein

R1 is hydrogen or C-|.g alkyl, in particular hydrogen, methyl or ethyl.

R3 is —CONH2, an imidazolyl, an imidazopyridinyl, an imidazopyridazinyl;in particular R̂ is —CONH2

R̂a is methyl, ethyl, butyl optionally substituted by halogen or C-1.4alkoxy, an unsubstituted phenyl or a phenyl substituted by halogen, aC-|.g alkyl optionally substituted by halogen or a C-1.4 alkoxy; or R̂ais a C2-6 alkenyl optionally substituted by halogen. Preferably, R̂a ismethyl, optionally substituted by halogen, an unsubstituted phenyl or aphenyl substituted by halogen.

In a particular embodiment, when R̂ is —CONH2 and R̂ is C-|.g alkyl, thecarbon atom to which R1 and Rβ are attached is preferably in the“S”-configuration.

A further aspect of the present invention consists in compounds havingthe formula (I-D1 or I-D2), their geometrical isomers, enantiomers,diastereomers and mixtures, or a pharmaceutically acceptable saltthereof,

wherein

R-I is hydrogen or C-|.g alkyl, in particular hydrogen; R3 is animidazolyl, an imidazopyridinyl or an imidazopyridazinyl. In oneembodiment, R̂ is 1 H-imidazol-1-yl, 1 H-imidazol-4-yl, 1H-imidazol-5-yl, imidazo[1,2-a]pyridin-3-yl orimidazo[1,2-b]pyridazin-3-yl. In a more specific embodiment, R̂ is 1H-imidazol-1-yl, 1 H-imidazol-4-yl, 1 H-imidazol-5-yl,imidazo[1,2-a]pyridin-3-yl; R̂a is hydrogen, C-|.g alkyl optionallysubstituted by halogen or C-1.4 alkoxy; aryl; or C2-g alkenyl optionallysubstituted by halogen. In a specific embodiment, R̂a is C-|.g alkyloptionally substituted by halogen; aryl; or C2-6 alkenyl optionallysubstituted by halogen. In a more specific embodiment R̂a is C-|.g alkyloptionally substituted by halogen; or aryl; e.g., propyl or phenyl; withthe proviso that when R̂ and R̂a are hydrogen, R̂ is not2-phenylimidazo[1,2-a]pyridin-3-yl.

A further aspect of the present invention consists in compounds havingthe formula (I-F1, I-F2 or I-F3), their geometrical isomers,enantiomers, diastereomers and mixtures, or a pharmaceuticallyacceptable salt thereof,

wherein

R-I is hydrogen or C-kg alkyl, preferably hydrogen, methyl or ethyl;more preferably, R̂ is hydrogen.

R3 is —CONH2, an imidazolyl, an imidazopyridinyl or animidazopyridazinyl; in a more specific embodiment R3 is —CONH2, 1H-imidazol-1-yl, 1 H-imidazol-4-yl, 1 H-imidazol-5-yl,imidazo[1,2-a]pyridin-3-yl or imidazo[1,2-b]pyridazin-3-yl. R̂b ishydrogen; halogen; nitro; cyano; C1.4 alkyl optionally substituted byhalogen; C-1.4 alkoxy optionally substituted by halogen. In a morespecific embodiment R̂ is hydrogen, halogen or cyano, more specificallyhalogen.

In a particular embodiment, when R̂ is —CONH2 and R̂ is C-|.g alkyl, thecarbon atom to which R1 and Rβ are attached is preferably in the“S”-configuration.

A further aspect of the present invention consists in compounds havingthe formula (I-F4), their geometrical isomers, enantiomers,diastereomers and mixtures, or a pharmaceutically acceptable saltthereof,

wherein

R-I is hydrogen or C-kg alkyl, preferably hydrogen;

R3 is an imidazolyl, an imidazopyridinyl or an imidazopyridazinyl; morespecifically R̂ is 1 H-imidazol-1-yl, 1 H-imidazol-4-yl, 1H-imidazol-5-yl, imidazo[1,2-a]pyridin-3-yl orimidazo[1,2-b]pyridazin-3-yl. More specifically R̂ is 1 H-imidazol-4-ylor imidazo[1,2-a]pyridin-3-yl.

R̂b is hydrogen; halogen; nitro; cyano; C-1.4 alkyl optionallysubstituted by halogen; C-1.4 alkoxy optionally substituted by halogen;specifically R̂ is hydrogen, halogen or cyano.

In a particular embodiment, when R̂ is —CONH2 and R̂ is C-|.g alkyl, thecarbon atom to which R-I and R̂ are attached is preferably in the“S”-configuration.

A further aspect of the present invention consists in compounds havingeither of the formula (I-G1, I-G2 or I-G3), their geometrical isomers,enantiomers, diastereomers and mixtures, or a pharmaceuticallyacceptable salt thereof,

wherein

R-I is hydrogen or C-|.g alkyl; preferably hydrogen;

R3 is —CONH2, an imidazolyl, an imidazopyridinyl, an imidazopyridazinyl;in a more specific embodiment R̂ is —CONH2, 1 H-imidazol-1-yl, 1H-imidazol-4-yl, 1 H-imidazol-5-yl, imidazo[1,2-a]pyridin-3-yl orimidazo[1,2-b]pyridazin-3-yl. In a even more specific embodiment R3 isan 1 H-imidazol-4-yl or imidazo[1,2-a]pyridin-3-yl;

R4D is hydrogen; halogen; C-1.4 alkyl optionally substituted by halogen;C-1.4 alkoxy optionally substituted by halogen.

Specific compounds of the present invention are those selected from thegroup consisting of:(2S)-2-[3-(4-nitrophenyl)-5-oxoimidazolidin-1-yl]butanamide;(2S)-2-[3-(2,4-dinitrophenyl)-5-oxoimidazolidin-1-yl]butanamide;(2S)-2-(5-oxo-3-phenylimidazolidin-1-yl)butanamide;2-[5-(iodomethyl)-2-oxo-1,3-oxazolidin-3-yl]butanamide;2-(2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide;2-(2-oxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide;2-(4-methyl-2-oxo-2,5-dihydro-1 H-pyrrol-1-yl)butanamide;(2S)-2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)butanamide;2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)propanamide;2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl)butanamide;2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl)propanamide;2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)propanamide;2-(2-oxo-5-propyl-1,3-thiazolidin-3-yl)butanamide;2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)butanamide;2-(2-oxo-5-propyl-1,3-thiazolidin-3-yl)propanamide;(2S)-2-[2-oxo-5-(2,2,2-trifluoroethyl)-1,3-thiazolidin-3-yl]butanamide;1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}piperidin-2-one;1-(1H-imidazol-4-ylmethyl)-5-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-5-propylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-5-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpiperidin-2-one;1-(1H-imidazol-5-ylmethyl)-4-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpiperidin-2-one;1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}azepan-2-one;1-(1H-imidazol-5-ylmethyl)-5-propylazepan-2-one;5-propyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepan-2-one;5-phenyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepan-2-one;1-(1H-imidazol-5-ylmethyl)-6-propylazepan-2-one;1-(1H-imidazol-4-ylmethyl)-4-propylazepan-2-one;4-(1H-imidazol-4-ylmethyl)-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one;2-(5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl)acetamide;4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one;4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}hexahydro-5H-thieno[3,2-b]pyrrol-5-one;1-(1H-imidazol-4-ylmethyl)-1H-thieno[3,4-b]pyrrol-2(3H)-one;2-(6-chloro-2-0X0-1,3-benzothiazol-3(2H)-yl)acetamide;6-bromo-3-(1H-imidazol-1-ylmethyl)-1,3-benzothiazol-2(3H)-one;2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide;2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide;2-(6-fluoro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;2-(6-methyl-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;6-fluoro-3-(1H-imidazol-1-ylmethyl)-1,3-benzoxazol-2(3H)-one;1-(1H-imidazol-4-ylmethyl)pyrazolo[1,5-a]pyridin-2(1 H)-one;2-(6-chloro-3-oxo-3,4-dihydroisoquinolin-2(1 H)-yl)propanamide;5-chloro-2-(1H-imidazol-4-ylmethyl)-1,4-dihydroisoquinolin-3(2H)-one;2-(6-chloro-2-oxo-3,4-dihydroquinolin-1 (2H)-yl)acetamide;2-(6-bromo-2-oxo-3,4-dihydroquinolin-1 (2H)-yl)acetamide;1-(1H-imidazol-4-ylmethyl)-3,4-dihydroquinolin-2(1 H)-one;2-(6-iodo-2-oxo-3,4-dihydroquinolin-1 (2H)-yl)acetamide;2-(6-cyano-2-oxo-3,4-dihydroquinolin-1 (2H)-yl)acetamide;7-chloro-2-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one;7-chloro-2-(1H-imidazol-4-ylmethyl)-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one;7-chloro-3-(1H-imidazol-4-ylmethyl)-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one;and7-chloro-3-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one.

In some embodiments, compounds of the present invention are thoseselected from the group consisting of:1-(1H-imidazol-4-ylmethyl)-5-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-5-propylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-5-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpiperidin-2-one;1-(1H-imidazol-5-ylmethyl)-4-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpiperidin-2-one; 1-(1H-imidazol-4-ylmethyl)-1H-thieno[3,4-b]pyrrol-2(3H)-one;6-bromo-3-(1H-imidazol-1-ylmethyl)-1,3-benzothiazol-2(3H)-one;2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide; and5-chloro-2-(1H-imidazol-4-ylmethyl)-1,4-dihydroisoquinolin-3(2H)-one.

The following paragraphs provide definitions of the various chemicalmoieties that make up the compounds according to the invention and areintended to apply uniformly through-out the specification andembodiments unless an otherwise expressly set out definition provides abroader definition.

“C-|_β alkyl” refers to alkyl groups having 1 to 6, or 1 to 4 carbonatoms. This term is exemplified by groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl,trifluoromethyl and the like. “Aryl” refers to an unsaturated aromaticcarbocyclic group of from 6 to 14 carbon atoms having a single ring(e.g., phenyl) or multiple condensed rings (e.g., naphthyl). Preferredaryl include phenyl, naphthyl, phenantrenyl and the like.

“Heterocycle” refers to a saturated or unsaturated ring systemcontaining, in addition to carbon atoms, at least one hetero atom, suchas nitrogen, oxygen and/or sulfur. “Heterocycle” includes both“heteroaryl” and “heterocycloalkyl”.

“Heteroaryl” refers to a monocyclic heteroaromatic, or a bicyclic or atricyclic fused-ring heteroaromatic group. Particular examples ofheteroaromatic groups include optionally substituted pyridyl, pyrrolyl,furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadia-zolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl,1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl,[2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl,isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl,imidazopyridinyl, benzothiazolyl, benzoxazolyl, quinolizinyl,quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl,pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl,quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl,5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl,xanthenyl, benzoquinolyl, imidazopyrimidinyl, imidazopyridazinyl,imidazothiazolyl or imidazothiadiazolyl.

“C2-6 alkenyl” refers to alkenyl groups preferably having from 2 to 6carbon atoms and having at least 1 or 2 sites of alkenyl unsaturation.Preferable alkenyl groups include ethenyl (vinyl, —CH═CH2), n-2-propenyl(allyl, —CH2CH═CH2) and the like.

“C2-6 alkynyl” refers to alkynyl groups preferably having from 2 to 6carbon atoms and having at least 1-2 sites of alkynyl unsaturation,preferred alkynyl groups include ethynyl (—C≡CH), propargyl (—CH2C≡CH),and the like.

“C3.8 cycloalkyl” refers to a saturated carbocyclic group of from 3 to 8carbon atoms having a single ring (e.g., cyclohexyl) or multiplecondensed rings (e.g., norbornyl). Preferred cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl and thelike.

“Heterocycloalkyl” refers to a C3.8 cycloalkyl group according to thedefinition above, in which 1 to 3 carbon atoms are replaced by heteroatoms chosen from the group consisting of O, S, NR, R being defined ashydrogen or C-|.g alkyl.

“Alkoxy” refers to the group —O—R where R includes “C-ng alkyl”, “C2-6alkenyl”, “C2-6 alkynyl”, “C3.8 cycloalkyl”, “heterocycloalkyl”, “aryl”,“heteroaryl”.

“Amino” refers to the group —NRR′ where each R, R′ is independentlyhydrogen, “C-|.g alkyl”, “C2-6 alkenyl”, “C2-6 alkynyl”, “C3-8cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”, and where R andR′, together with the nitrogen atom to which they are attached, canoptionally form a 3-8-membered heterocycloalkyl ring.

“Amido” refers to the group —C(═O)NRR′ where each R, R′ is independentlyhydrogen, “C-|_5 alkyl”, “C2-6 alkenyl”, “C2-6 alkynyl”, “C3.8cycloalkyl”, “heterocycloalkyl”, “aryl”,

“heteroaryl”, and where R and R′, together with the nitrogen atom towhich they are attached, can optionally form a 3-8-memberedheterocycloalkyl ring.

“Acylamino” refers to the group —NRC(O)R′ wherein R and R′ are asdefined hereabove for the amino group.

“Ureido” refers to the group —NR″C(O)NRR′ wherein R and R′ are asdefined hereabove for the amino group, and R″ is as defined hereabove.“Sulfanyl” refers to the group —SR where R is “C-|.g alkyl”, “C2-6alkenyl”, “C2-6 alkynyl”, “C3.8 cycloalkyl”, “heterocycloalkyl”, “aryl”or “heteroaryl”.

“Sulfinyl” refers to the group —S(═O)R where R is “C-|.g alkyl”, “C2-6alkenyl”, “C2-6 alkynyl”, “C3.8 cycloalkyl”, “heterocycloalkyl”, “aryl”or “heteroaryl”.

“Sulfonyl” refers to the group —S(═O)2R where R is “C-|.g alkyl”, “C2-6alkenyl”,

“C2-6 alkynyl”, “C3.8 cycloalkyl”, “heterocycloalkyl”, “aryl” or“heteroaryl”.

“Halogen” refers to fluoro, chloro, bromo and iodo atoms.

“Substituted or unsubstituted”: Unless otherwise constrained by thedefinition of the individual substituent, the above set out groups, like“alkyl”, “alkenyl”, “alkynyl”, “aryl” and

“heteroaryl” etc. groups can optionally be substituted with from 1 to 5substituents selected from the group consisting of “C-|.g alkyl”, “C2-6alkenyl”, “C2-6 alkynyl”, “cycloalkyl”, “heterocycloalkyl”, “amino”,“amido”, “acylamino”, “ureido”, “aryl”, “heteroaryl”, “alkoxy”,“halogen”, cyano, hydroxy, mercapto, nitro, “amido”, “sulfanyl”,“sulfinyl”, “sulfonyl” and the like.

The acid addition salt form of a compound of formula (I) that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, a hydrohalicsuch as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric andthe like; or an organic acid, such as, for example, acetic,trifluoroacetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic,succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like.

The compounds of formula (I) containing acidic protons may be convertedinto their therapeutically active, non-toxic base addition salt forms,e.g. metal or amine salts, by treatment with appropriate organic andinorganic bases. Appropriate base salt forms include, for example,ammonium salts, alkali and earth alkaline metal salts, e.g. lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e.g. N-methyl-D-glucamine, hydrabamine salts, and saltswith amino acids such as, for example, arginine, lysine and the like.

Conversely said salt forms can be converted into the free forms bytreatment with an appropriate base or acid.

Compounds of the formula (I) and their salts can be in the form of asolvate, which is included within the scope of the present invention.Such solvates include for example hydrates, alcoholates and the like.

Many of the compounds of formula (I) and some of their intermediateshave at least one stereogenic center in their structure. Thisstereogenic center may be present in a R or a S configuration, said Rand S notation is used in correspondence with the rules described inPure Appl. Chem., 45 (1976) 11-30.

The invention also relates to all stereoisomeric forms such asenantiomeric and diastereoisomeric forms of the compounds of formula (I)or mixtures thereof (including all possible mixtures of stereoisomers).With respect to the present invention reference to a compound orcompounds is intended to encompass that compound in each of its possibleisomeric forms and mixtures thereof, unless the particular isomeric formis referred to specifically.

Compounds according to the present invention may exist in differentpolymorphic forms. Although not explicitly indicated in the aboveformula, such forms are intended to be included within the scope of thepresent invention.

Some of the compounds of formula (I) may also exist in tautomeric forms.Such forms although not explicitly indicated in the above formula areintended to be included within the scope of the present invention.

The invention also includes within its scope pro-drug forms of thecompounds of formula (I) and its various sub-scopes and sub-groups.

In a specific embodiment, the present invention concerns a compoundselected from the group consisting of:(2S)-2-[3-(4-nitrophenyl)-5-oxoimidazolidin-1-yl]butanamide;(2S)-2-[3-(2,4-dinitrophenyl)-5-oxoimidazolidin-1-yl]butanamide;(2S)-2-(5-oxo-3-phenylimidazolidin-1-yl)butanamide;2-[5-(iodomethyl)-2-oxo-1,3-oxazolidin-3-yl]butanamide;2-(2-oxo-2,5-dihydro-1 H-pyrrol-1-yl)butanamide;2-(2-oxo-4-phenyl-2,5-dihydro-1 H-pyrrol-1-yl)butanamide;2-(4-methyl-2-oxo-2,5-dihydro-1 H-pyrrol-1-yl)butanamide;(+)-(2S)-2-(2-oxo-4-propyl-2,5-dihydro-1 H-pyrrol-1-yl)butanamide;(2S)-2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)butanamide;2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)propanamide;2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl)butanamide;2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl)propanamide;2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)propanamide;2-(2-oxo-5-propyl-1,3-thiazolidin-3-yl)butanamide;2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)butanamide;2-(2-oxo-5-propyl-1,3-thiazolidin-3-yl)propanamide;(2S)-2-[2-oxo-5-(2,2,2-trifluoroethyl)-1,3-thiazolidin-3-yl]butanamide;1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}piperidin-2-one;1-(1 H-imidazol-4-ylmethyl)-5-propylpiperidin-2-one; 1-(1H-imidazol-1-ylmethyl)-5-propylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-propylpiperidin-2-one; 1-(1H-imidazol-1-ylmethyl)-5-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpiperidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpiperidin-2-one; 1-(1H-imidazol-5-ylmethyl)-4-propylpiperidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-propylpiperidin-2-one;1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}azepan-2-one;1-(1 H-imidazol-5-ylmethyl)-5-propylazepan-2-one;5-propyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepan-2-one;1-(1 H-imidazol-5-ylmethyl)-5-phenylazepan-2-one;5-phenyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepan-2-one;1-(1 H-imidazol-5-ylmethyl)-6-propylazepan-2-one; 1-(1H-imidazol-4-ylmethyl)-4-propylazepan-2-one; 4-(1H-imidazol-4-ylmethyl)-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one;2-(5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl)acetamide;4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one;4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}hexahydro-5H-thieno[3,2-b]pyrrol-5-one;1-(1 H-imidazol-4-ylmethyl)-1 H-thieno[3,4-b]pyrrol-2(3H)-one;2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;2-(2-OXO-1,3-benzothiazol-3(2H)-yl)acetamide;2-(6-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide; 6-bromo-3-(1H-imidazol-1-ylmethyl)-1,3-benzothiazol-2(3H)-one;6-bromo-3-(2-oxopropyl)-1,3-benzothiazol-2(3H)-one;2-(6-nitro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide;2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide;2-(6-fluoro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;2-(6-methyl-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide; 6-fluoro-3-(1H-imidazol-1-ylmethyl)-1,3-benzoxazol-2(3H)-one; 1-(1H-imidazol-4-ylmethyl)pyrazolo[1,5-a]pyridin-2(1 H)-one;2-(6-chloro-3-oxo-3,4-dihydroisoquinolin-2(1 H)-yl)propanamide;5-chloro-2-(1 H-imidazol-4-ylmethyl)-1,4-dihydroisoquinolin-3(2H)-one;2-(6-chloro-2-oxo-3,4-dihydroquinolin-1 (2H)-yl)acetamide;2-(6-bromo-2-oxo-3,4-dihydroquinolin-1 (2H)-yl)acetamide; 1-(1H-imidazol-4-ylmethyl)-3,4-dihydroquinolin-2(1 H)-one;2-(6-iodo-2-oxo-3,4-dihydroquinolin-1 (2H)-yl)acetamide;2-(6-cyano-2-oxo-3,4-dihydroquinolin-1 (2H)-yl)acetamide;7-chloro-2-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one;7-chloro-2-(1H-imidazol-4-ylmethyl)-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one;7-chloro-3-(1H-imidazol-4-ylmethyl)-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one; and7-chloro-3-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one.

xvi) UK Patent 1,039,113

The new compounds according to the present invention are N-substitutedlactams of the general formula:

wherein N is a whole number of from 3 to 5 and R represents a

radical in which m is 0, 1 or 2 and R′ is a hydrogen atom or an alkyl,cycloalkyl, alkenyl or alkynyl radical, which may contain 3 to 6 carbonatoms, or an aryl radical, and R″ is a hydrogen atom or an alkylradical, or both R′ and R″, together with the nitrogen atom to whichthey are attached, form a heterocyclic ring, such as 5 a pyrrolidinering.

xvii) UK Patent 1,309,692

According to the present invention, there are provided new N-substitutedlactams of the general formula:

wherein X is a hydrogen atom or an alkyl, alkenyl or alkynyl radicalcontaining 1 to 6 carbon atoms, p is a whole number of from 1 to 6, Y isa hydrogen atom or an alkyl, alkenyl or alkynyl radical containing 1 to6 carbon atoms or a cycloalkyl radical and R′ and R″, which may be thesame or different, are hydrogen atoms or alkyl, alkenyl, alkynyl,cycloalkyl or aryl radicals or R′ and R″, together with the nitrogenatom to which they are attached, form a heterocyclic radical which maycontain further heteroatoms, with the proviso that at least one of thesymbols X and Y is other than a hydrogen atom.

Antipsychotics

The antipsychotics suitable for use in the present invention may be anyantipsychotic drugs or agents or pharmaceutically acceptable salts,hydrates, solvates, polymorphs or prodrugs thereof.

(1) “Typical” and “Atypical” Antipsychotics

Among the antipsychotics or pharmaceutically acceptable salts, hydrates,solvates, polymorphs and prodrugs thereof that are useful in the methodsand compositions of this invention are atypical and typicalantipsychotics.

In some embodiments, the antipsychotic is an atypical antipsychotic orpharmaceutically acceptable salts, hydrates, solvates, prodrugs andpolymorphs thereof. Atypical antipsychotics offer several clinicalbenefits including, for example, superior side effect profiles,particularly with regard to extrapyramidal side effects (EPS). Atypicalantipsychotics typically differ from typical antipsychotics in their“limbic-specific” dopamine type 2 (D2)-receptor binding. Atypicalantipsychotics, also display a high ratio of serotonin type 2(5-HT2)-receptor binding to D2 binding. Atypical antipsychotics havehigh affinity for the 5-HT2-receptor and function as antagonists ofserotonin for the 5-HT2-receptor.

Examples of atypical antipsychotics include, but are not limited to:Aripiprazole,7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-di-hydrocarbostyril(commercially available from Bristol-Meyers Squibb Co., Princeton, N.J.under the trade name Ability®) is disclosed in U.S. Pat. Nos. 4,734,416and 5,006,528, which are incorporated herein by reference. Exemplaryformulations and dosages of aripiprazole suitable for use in treatingschizophrenia and bipolar disorder are described in U.S. Pat. Nos.6,977,257; 7,115,587; and 7,550445, which are herein incorporated byreference in their entirety.

Asenapine, trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole (under trade name Saphris® orSycrest®) is disclosed in U.S. Pat. Nos. 4,145,434 and 5,763,476, whichare herein incorporated by reference in their entirety. An orthorhombiccrystal form of asenapine is described in U.S. Pat. No. 7,741,358, whichis also incorporated herein by reference. Clozapine,8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]-diazepine(commercially available from Mylan Pharmaceuticals, Morgantown, W. Va.under the trade name Mylan®) is disclosed in U.S. Pat. No. 3,539,573,which is herein incorporated by reference. Clinical efficacy ofClozapine in the treatment of schizophrenia has previously beendisclosed. Hanes, et al., Psychopharmacol. Bull., 24, 62 (1988).

Iloperidone,1-[4-[3-[4-(6-Fluoro-1,2-benzisexazol-3-yl)-1)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone(under trade name Fanapt®) is disclosed in EP Patent EP402644, which isincorporated herein by reference. The use of iloperidone in treatingpsychotic symptom and exemplary dosages of iloperidone suitable for suchtreatment are disclosed in U.S. Pat. No. RE39198, which is incorporatedherein by reference.

Olanzapine, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, disclosed in U.S. Pat. No. 5,229,382(commercially available from Eli Lilly, Indianapolis, Ind. under thetrade name Zyprexa®) which is hereby incorporated by reference, as beinguseful for the treatment of schizophrenia, schizophreniform disorder,acute mania, mild anxiety states, and psychosis. The use of olanzapinein treating schizophrenia and exemplary dosages of olanzapine for suchuse are disclosed in U.S. Pat. Nos. 5,625,897, 5,627,178, 5,817655,5,919485 and 6960577. Olanzapine polymorphs are disclosed in U.S. Pat.No. 5,736,541, incorporated herein by reference. Olanzapine hydrateforms are disclosed in U.S. Pat. No. 6,251,895, incorporated herein byreference.

Lurasidone,(3aR,4S,7R7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)-piperazin-1-yl-methyl]cyohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione(developed by Dainippon Sumitomo Pharma Co., Ltd. under trade nameLatuda®) is disclosed in U.S. Pat. No. 5,532,372, incorporated herein byreference. Paliperidone,3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4Hpyrido[1,2-a]pyrimidin-4-one(developed by Janssen Pharmaceutica under the trade name Invega® orInvega Sustenna®), is disclosed in EP Patent 368388. The use ofpaliperidone in treating psychosis and exemplary formulations for suchuse are disclosed in U.S. Pat. Nos. 5,158,952, 5,254,556, 5,352459,6,077,843 and 6,555,544, all of which are incorporated herein byreference.

Quetiapine, 5-[2-(4-dibenzo[b,f] [1,4]thiazepin-11-yl-1-piperazinyl)-eth-oxy]ethanol (commercially availablefrom Astra Zeneca, Wilmington, Del. under the tradename Seroquel®) itsactivity in assays which demonstrate utility in the treatment ofschizophrenia are disclosed in U.S. Pat. No. 4,879,288, which is hereinincorporated by reference. Exemplary formulations of quetiapine for usein treating schizophrenia and bipolar disorder are disclosed in U.S.Pat. No. 5,948,437, incorporated herein by reference.

Risperidone,3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-4-one(commercially available from Janssen under the trade name Risperdal®)and its use in the treatment of psychotic diseases are disclosed in U.S.Pat. No. 4,804,663, which is herein incorporated by reference.

Sertindole, 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]imidazolidin-2-one, is described inU.S. Pat. No. 4,710,500. Its use in the treatment of schizophrenia isdescribed in U.S. Pat. Nos. 5,112,838 and 5,238,945. U.S. Pat. Nos.4,710,500; 5,112,838; and 5,238,945 are herein incorporated by referencein their entirety.

Ziprasidone,5-[2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one,(commercially available from Pfizer Inc., New York, N.Y. under the tradename Geodon®) is disclosed in U.S. Pat. Nos. 4,831,031 and 5,312,925 andits activity in assays which demonstrate utility in the treatment ofschizophrenia are described in U.S. Pat. No. 4,831,031, all of which areherein incorporated by reference.

Surmontil (trimipramine maleate),5-(3-dimethylamino-2-methylpropyl)-10,11-dihydro-5H-dibenz (b,f) azepineacid maleate (Commercially available from Odyssey Pharmaceuticals, Inc.,North Hanover, N.J. under the trade name Surmotil®).

In some embodiment, the antipsychotic for the methods and compositionsof this invention is selected from aripiprazole, olanzapine andziprasidone, or pharmaceutically acceptable salts, hydrates, solvates,polymorphs or prodrugs thereof.

In some embodiments of the invention, the antipsychotic is a typicalantipsychotic. Such typical antipsychotics include, but are not limitedto, acepromazine, benperidol, bromazepam, bromperidol, chlorpromazine,chlorprothixene, clotiapine, cyamemazine, diazepam, dixyrazine,droperidol, flupentixol, fluphenazine, fluspirilene, haloperidol,heptaminol, isopropamide iodide, levomepromazine, levosulpiride,loxapine, melperone, mesoridazine, molindone, oxypertine, oxyprothepine,penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone,pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl,pyridoxine, sulpiride, sultopride, tetrabenazine, thioproperazine,thioridazine, tiapride, tiotixene, trifluoperazine, triflupromazine,trihexyphenidyl, and zuclopenthixol, and pharmaceutically acceptablesalts, hydrates, solvates, prodrugs and polymorphs thereof.

(2) Antipsychotics Displaying Various Pharmacology/Mechanisms

Suitable antipsychotics or pharmaceutically acceptable salts, hydrates,solvates or polymorphs thereof for the present invention may be selectedfrom compounds/agents that are dopaminergic agents, glutamatergicagents, NMDA receptor positive allosteric modulators, glycine reuptakeinhibitors, glutamate reuptake inhibitor, metabotropic glutamatereceptors (mGluRs) agonists or positive allosteric modulators (PAMs)(e.g., mGluR2/3 agonists or PAMs), glutamate receptor glur5 positiveallosteric modulators (PAMs), M1 muscarinic acetylcholine receptor(mAChR) positive allosteric modulators (PAMs), histamine H3 receptorantagonists, AMPA/kainate receptor antagonists, ampakines (CX-516),glutathione prodrugs, noradrenergic agents, serotonin receptormodulators, cholinergic agents, cannabinoid CB1 antagonists, neurokinin3 antagonists, neurotensin agonists, MAO B inhibitors, PDE10 inhibitors,nNOS inhibits, neurosteroids, and neurotrophic factors.

In some embodiments, the antipsychotic is a dopaminergic agent selectedfrom dopamine D1 receptor antagonists or agonists (for example,dihydrexidine, A77636 and SKF81297), dopamine D₂ receptor antagonists orpartial agonists (e.g., some typical and atypical antipsychotics),dopamine D3 receptor antagonists or agonists (for example, 533084,SB-277011-A, AVE5997 and (±)-PD128907), dopamine D4 receptor antagonists(for examples, clozapine and sonepiprazole (U-101387 or PNU-101387G)).

In some embodiments, the antipsychotic is a glutamatergic agent selectedfrom NMDA receptor positive allosteric modulators (e.g., glycine,D-cycloserine and D-serine), glycine reuptake inhibitors (e.g.,N-(3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl) sarcosine andglycyldodecylamide), glutamate reuptake inhibitor (e.g., excitatoryamino-acid transporters EAAT3 antagonists), metabotropic glutamatereceptors agonists (e.g., LY-354740), AMPA/kainate receptor antagonists(e.g., LY-293558, GYKI52466 and LY-326325), ampakines (CX-516), andglutathione prodrugs.

In some embodiments, the antipsychotic is a noradrenergic agent selectedfrom alpha-2 adrenergic receptor agonists or antagonists (e.g.,guanfacine, clozapine and risperidone) and COMT inhibitors (e.g.,tolcapone).

In some embodiments, the antipsychotic is a serotonin receptor modulatorselected from 5-HT_(2A) receptor antagonists, 5-HT_(1A) receptor partialagonists, 5-HT_(2C) agonists, and 5-HT6 antagonists (e.g., some atypicalantipsychotics).

In some embodiments, the antipsychotic is a cholinergic agent selectedfrom alpha-7 nicotinic receptor agonists (e.g.,3-2,4-dimethoxybenzylidene anabaseine (DMXB-A or GTS-21)), alpha4-beta2nicotinic receptor agonists (e.g., SIB-1553A), allosteric modulators ofnicotinic receptors and acetylcholinesterase inhibitors, muscarinicreceptor agonists and antagonists (e.g., N-desmethylclozapine,xanomeline, PTAC, and BuTAC).

In some embodiments, the antipsychotic is selected from cannabinoid CB1antagonists (e.g., SR141716), neurokinin 3 antagonists (e.g., osanetant(SR-142801) and talnetant), neurotensin agonists (e.g., SR-48692), MAO Binhibitors (e.g., Selegiline (deprenyl) and rasagiline), PDE10inhibitors (e.g., Papaverine), NNOS inhibits (e.g., methylene blue,LNOARG, L-NAME, and 7-nitroindazole), neurosteroids (e.g.,dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEA-S),pregnenolone (PREG) and pregnenolone sulfate (PREGS)), and neurotrophicfactors (e.g., nerve growth factor (NGF), brain-derived neurotrophicfactor (BDNF) and neurotrophin (NT)-3/4/5)).

(3) Antipsychotics Useful for Treating Symptoms of Schizophrenia orBipolar Disorder (in Particular, Mania)

In some embodiments, the antipsychotics or pharmaceutically acceptablesalts, hydrates, solvates, polymorphs and prodrugs thereof that areuseful in the methods and compositions of this invention include thosethat are useful in treating one or more signs or symptoms ofschizophrenia or bipolar disorder (in particular, mania).

Schizophrenia is characterized by psychological symptoms such asperception (hallucinations), ideation, reality testing (delusions),thought processes (loose associations), feeling (flatness, inappropriateeffect), behavior (catatonia, disorganization), attention,concentration, motivation (avolition, impaired intentions and planning)and judgment (see for example Diagnostic and Statistical Manual ofMental Disorders IV, American Psychiatric Association). In general, thesymptoms of schizophrenia are divided into positive and negativesymptoms with hallucinations and delusions being positive features, andfeatures such as flatness, poverty of speech and impaired executivefunctions representing negative symptoms. Clinical rating scales such asPositive and Negative Syndrome Scale and Scale for the Assessment ofNegative Symptoms provide criteria to differentiate between, and rate,positive and negative symptoms. Frequently included in the descriptionof negative symptoms are the cognitive deficits schizophrenic andschizotypical patients suffer from. These include impairment inattention, verbal fluency, executive functions such as planning, workingmemory and visual and verbal learning and memory. These types ofcognitive dysfunction can be measured with a variety of tests, such asVisual Search, Verbal Fluency, Wisconsin Card Sorting, Trail Making—PartB, Symbol Digit, Hopkins Verbal Learning, Digit Span, Stroop-Color-Wordand Attentional Capacity. MATRICS consensus neuropsychological testbattery which includes tests of working memory, speed of processing,attention, verbal learning, visual learning, reasoning and problemsolving and social cognition. Moreover, it has been found that cognitivemeasures predict work function and overall outcome as assessed by theGlobal Assessment Scale and Quality of Life Scale. Several studies havenow demonstrated that neuropsychological functions, reflecting severalnegative and cognitive symptoms of the disease, may be more impaired inmale schizophrenic patients when compared to female patients. Further,there are a number of other psychiatric diseases such as schizotypicaland schizoaffective disorder, other acute- and chronic psychoses andbipolar disorder which have an overlapping symptomatology withschizophrenia. Any compounds or pharmaceutically acceptable salts,hydrates, solvates, polymorphs and prodrugs thereof that are useful intreating at least one of the signs or symptoms of schizophrenia orbipolar disorder (in particular, mania), including, for example, thoserecited above, are useful in the methods and compositions of thisinvention.

Among the antipsychotics or pharmaceutically acceptable salts, hydrates,solvates, polymorphs and prodrugs thereof that are useful in the methodsand compositions of this invention are those disclosed, for example, inU.S. Pat. Nos. 4,734,416; 5,006,528; 4,145,434; 5,763,476; 3,539,573;5,229,382; 5,532,372; 4,879,288; 4,804,663; 4,710,500; 4,831,031; and5,312,925, and EP Patents EP402644 and EP368388, and thepharmaceutically acceptable salts, hydrates, solvates, polymorphs andprodrugs thereof.

In some embodiments, the antipsychotics useful in this invention includethose compounds/agents disclosed, for example, in U.S. Patents or PatentPublications US20020052401A1; US20020091118A1; US20020091119A1;US20020094986A1; US20020123490A1; US20020147194A1; US20020156089A1;US20020165217A1; US20030008806A1; US20030008892A1; US20030013887A1;US20030018047A1; US20030027812A1; US20030032579A1; US20030130303A1;US20030158208A1; US20030162766A1; US20030181458A1; US20030191176A1;US20030208081A1; US20030232841A1; US20030235631A1; US20040001895A1;US20040006135A1; US20040029876A1; US20040039022A1; US20040048869A1;US20040049039A1; US20040082597A1; US20040106603A1; US20040110817A1;US20040116443A1; US20040132713A1; US20040138232A1; US20040162293A1;US20040162294A1; US20040167200A1; US20040204414A1; US20040204415A1;US20040204445A1; US20040204453A1; US20040209887A1; US20040220184A1;US20040220274A1; US20040229874A1; US20040229911A1; US20040242587A1;US20040254193A1; US20040259859A1; US20040266781A1; US20040266815A1;US20050004106A1; US20050004137A1; US20050009927A1; US20050014764A1;US20050014848A1; US20050026937A1; US20050026946A1; US20050032837A1;US20050038036A1; US20050043292A1; US20050070577A1; US20050080099A1;US20050080100A1; US20050101613A1; US20050107425A1; US20050113437A1;US20050143403A1; US20050171086A1; US20050171095A1; US20050182049A1;US20050203296A1; US20050209250A1; US20050215571A1; US20050227980A1;US20050227981A1; US20050234065A1; US20050245521A1; US20050245543A1;US20050250803A1; US20050256112A1; US20050256162A1; US20050282811A1;US20050282816A1; US20050288304A1; US20060014733A1; US20060019998A1;US20060025421A1; US20060047114A1; US20060052373A1; US20060058361A1;US20060069087A1; US20060084692A1; US20060094719A1; US20060148807A1;US20060166974A1; US20060166998A1; US20060173179A1; US20060183763A1;US20060217398A1; US20060229455A1; US20060270656A1; US20070015763A1;US20070027178A1; US20070049613A1; US20070054913A1; US20070093509A1;US20070155779A1; US20070185097A1; US20070213337A1; US20070224636A1;US20080045512A1; US20080096955A1; US20080139567A1; US20080167319A1;US20080176925A1; US20080207897A1; US20080269110A1; US20080269246A1;US20080305161A1; US20080318926A1; US20090011994A1; US20090023756A1;US20090093512A1; US20090131433A1; US20090176829A1; US20090197859A1;US20090215857A1; US20090298811A1; US20100004259A1; US20100029684A1;US20100113465A1; US20100130501A1; US20100222353A1; US20100249128A1;US20100324043A1; US20110003759A1; US20110028520A1; US20110034484A1;US20110144060A1; US20110144159A1; US20110152334A1; US20110160220A1;US20110166160A1; US20110230493A1; US20110269745A1; US20110319439A1;US20110319449A1; US20120028961A1; US20120108588A1; US20120142729A1;US20120202809A1; US20120214784A1; US20120214791A1; US20120220568A1; U.S.Pat. 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Method of Treating Schizophrenia or Bipolar Disorder (in Particular,Mania) with the Administration of a SV2A Inhibitor and an Antipsychoticor Pharmaceutically Acceptable Salts Thereof

In one aspect, the invention provides methods for treating a subjectsuffering from schizophrenia or bipolar disorder (in particular, mania),or at risk thereof, by administering a SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate or polymorph thereofin combination with an antipsychotic or a pharmaceutically acceptablesalt, hydrate, solvate or polymorph thereof. In some embodiments, themethods of this invention treat one or more positive and/or negativesymptoms, as well as cognitive impairment, associated with schizophreniaIn some embodiments, the methods of this invention treat one or moresymptoms, as well as cognitive impairment, associated with bipolardisorder (in particular, mania).

The SV2A inhibitor and the antipsychotic suitable for the method of thisinvention may be selected from any of those as described above. In someembodiments, the SV2A inhibitor is selected from any of those describedabove; and the antipsychotic is selected from (1) atypical and typicalantipsychotics (such as those described above); (2) agents that aredopaminergic agents (such as dopamine D1 receptor antagonists oragonists, dopamine D₂ receptor antagonists or partial agonists, dopamineD3 receptor antagonists or partial agonists, dopamine D4 receptorantagonists), glutamatergic agents, NMDA receptor positive allostericmodulators, glycine reuptake inhibitors, glutamate reuptake inhibitor,metabotropic glutamate receptors (mGluRs) agonists or positiveallosteric modulators (PAMs) (e.g., mGluR2/3 agonists or PAMs),glutamate receptor glur5 positive allosteric modulators (PAMs), M1muscarinic acetylcholine receptor (mAChR) positive allosteric modulators(PAMs), histamine H3 receptor antagonists, AMPA/kainate receptorantagonists, ampakines (CX-516), glutathione prodrugs, noradrenergicagents (such as alpha-2 adrenergic receptor agonists or antagonists andCOMT inhibitors), serotonin receptor modulators (such as 5-HT_(2A)receptor antagonists, 5-HT_(1A) receptor partial agonists, 5-HT_(2C)agonists, and 5-HT6 antagonists), cholinergic agents (such as alpha-7nicotinic receptor agonists, alpha4-beta2 nicotinic receptor agonists,allosteric modulators of nicotinic receptors and acetylcholinesteraseinhibitors, muscarinic receptor agonists and antagonists), cannabinoidCB1 antagonists, neurokinin 3 antagonists, neurotensin agonists, MAO Binhibitors, PDE10 inhibitors, nNOS inhibits, neurosteroids, andneurotrophic factors, including, e.g., those specific such agents asdescribed above, and (3) any compounds that are useful in treating oneor more sign or symptoms of schizophrenia or bipolar disorder (inparticular, mania) (including, e.g., the agents disclosed in any of theabove-listed patents or patent application publications), andpharmaceutically acceptable salts, hydrates, solvates, polymorphs orprodrugs thereof. In some embodiments, the SV2A inhibitor is selectedfrom the group consisting of levetiracetam, seletracetam, andbrivaracetam or derivatives or analogs or pharmaceutically acceptablesalts, or solvates, or hydrates, or polymorphs, or prodrugs thereof andthe antipsychotic is an atyptical antipsychotic selected from, e.g.,aripiprazole, olanzapine and ziprasidone, and pharmaceuticallyacceptable salts, hydrates, solvates, polymorphs or prodrugs thereof. Insome embodiments, the SV2A inhibitor is selected from levetiracetam orderivatives or analogs or pharmaceutically acceptable salts, orsolvates, or hydrates, or polymorphs, or prodrugs thereof and theantipsychotic is an atyptical antipsychotic selected from, e.g.,aripiprazole, olanzapine and ziprasidone, and pharmaceuticallyacceptable salts, hydrates, solvates, polymorphs or prodrugs thereof.

In some embodiments, the subject that suffers schizophrenia or bipolardisorder (in particular, mania) is a human patient. The subject may be ahuman or other mammal such as a non-human primate, or rodent (e.g.,rat). In some embodiments, the subject is a human patient.

In some embodiments, the use of the SV2A inhibitors and pharmaceuticallyacceptable salts, hydrates, solvates and polymorphs thereof incombination with antipsychotics and their pharmaceutically acceptablesalts, hydrates, solvates and polymorphs may reduce the amount ofantipsychotics necessary for the treatment of schizophrenia or bipolardisorder (in particular, mania). In some embodiments, the subject thatsuffers schizophrenia or bipolar disorder (in particular, mania) is ahuman patient, and thus the use of the SV2A inhibitors reduce the sideeffects caused by antipsychotics without diminishing efficacy. Further,in some embodiments, the efficacy of a combination of the SV2Ainhibitors and antipsychotics and pharmaceutically acceptable salts,solvates, hydrates, and polymorphs thereof exceeds the efficacy ofeither drug administered alone at its optimal dose and thus, is animproved treatment for schizophrenia or bipolar disorder (in particular,mania).

It will be appreciated that compounds and agents used in thecompositions and methods of this invention preferably should readilypenetrate the blood-brain barrier when peripherally administered.Compounds which cannot penetrate the blood-brain barrier, however, canstill be effectively administered directly into the central nervoussystem, e.g., by an intraventricular or other neuro-compatible routes.

As used herein, administration of SV2A inhibitor and an antipsychotic orpharmaceutically acceptable salts, hydrates, solvates and polymorphsthereof “in combination” includes simultaneous administration and/oradministration at different times, such as sequential administration.Simultaneous administration of the SV2A inhibitor and the antipsychoticor their pharmaceutically acceptable salts, hydrates, solvates andpolymorphs can optionally be combined with supplemental doses of theSV2A inhibitor and/or the antipsychotic and their salts, hydrates,solvates and polymorphs. Simultaneous administration of drugsencompasses administration as co-formulation or, alternatively, asseparate compositions.

In accordance with this invention, the SV2A inhibitor and the psychotic,and pharmaceutically acceptable salts, solvates, hydrates, polymorphsthereof, can be administered to a subject via any suitable route orroutes. In some embodiments, the drugs are administered orally; however,administration intravenously, subcutaneously, intra-arterially,intramuscularly, intraspinally, rectally, intrathoracically,intraperitoneally, intracentricularly, or transdermally, topically, orby inhalation is also contemplated. The agents can be administeredorally, for example, in the form of tablets, troches, capsules, elixirs,suspensions, syrups, wafers, or the like, prepared by art recognizedprocedures. In certain embodiments, the SV2A inhibitor and theantipsychotic, and pharmaceutically acceptable salts, solvates,hydrates, polymorphs thereof, can be administered to a subject viadifferent routes. For example, the SV2A inhibitor or its salt, solvate,hydrate, or polymorph is administered intravenously and theantipsychotic or its salt, solvate, hydrate, or polymorph isadministered orally.

In some embodiments, the administration is a slow or extended release.The term “extended release” is widely recognized in the art ofpharmaceutical sciences and is used herein to refer to a controlledrelease of an active compound or agent from a dosage form to anenvironment over (throughout or during) an extended period of time, e.g.greater than or equal to one hour. An extended release dosage form willrelease drug at substantially constant rate over an extended period oftime or a substantially constant amount of drug will be releasedincrementally over an extended period of time. The term “extendedrelease” used herein includes the terms “controlled release,” “prolongedrelease,” “sustained release,” “delayed release,” or “slow release” asthese terms are used in the pharmaceutical sciences. In someembodiments, the extended release dosage is administered in the form ofa patch or a pump.

When a solid carrier is used for administration, the preparation may bein a tablet, placed in a hard gelatin capsule in powder or pellet form,or it may be in the form of a troche or lozenge. If a liquid carrier isused, the preparation may be in the forms of a syrup, emulsion, softgelatin capsule, or sterile injectable liquid such as an aqueous ornon-aqueous liquid suspension or solution.

Dosage schedules of the agents and compositions according to the methodsof the invention will vary according to the particular compound orcompositions selected, the route of administration, the nature of thecondition being treated, the age, and condition of the patient, thecourse, or stage of treatment, and will ultimately be at the discretionof the attending physician. It will be understood that the amount of theSV2A inhibitor and the antipsychotic and their pharmaceuticallyacceptable salts, hydrates, solvates and polymorphs thereof administeredwill be amounts effective to produce a desired biological effect, suchas beneficial results, including clinical results. It will be understoodthat an effective amount can be administered in more than one dose andover a course of treatment.

Desired duration of administration of the SV2A inhibitor and theantipsychotic and their pharmaceutically acceptable salts, hydrates,solvates and polymorphs thereof can be determined by routineexperimentation by one skilled in the art. For example, the SV2Ainhibitor and the antipsychotic and their pharmaceutically acceptablesalts, hydrates, solvates and polymorphs thereof may be administered fora period of 1-4 weeks, 1-3 months, 3-6 months, 6-12 months, 1-2 years,or more, up to the lifetime of the patient.

It is known in the art that normalization to body surface area is anappropriate method for extrapolating doses between species. The humanequivalent dose (HED) for this dosage can be estimated using thefollowing formula that accounts for differences in body surface area(see Estimating the Safe

Starting Dose in Clinical Trials for Therapeutics in Adult HealthyVolunteers, December 2002, Center for Biologics Evaluation andResearch):

HED=animal dose×(Km animal/Km human)

where the Km factor is body weight divided by body surface area (Km rathas been determined as 6, and Km human is 37; see Reagan-Saw, Nihal,Ahmad, 2007). Thus, a dosage of 10 mg/kg in rats is equivalent to 1.6mg/kg in humans (10 mg/kg×(6/37)=1.6 mg/kg). For human subjects, tocalculate a dose in mg from the dose in mg/kg, the dose in mg/kg ismultiplied by a typical adult weight of 70 kg.

In certain embodiments of the invention, the dose of the SV2A inhibitoror its pharmaceutically acceptable salt, hydrate, solvate or polymorphis 0.1 to 5 mg/kg/day (which, given a typical human subject of 70 kg, is7 to 350 mg/day).

In certain embodiments of the invention, the SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate and polymorph thereofcan be administered at doses according to, for example, U.S. patentapplication Ser. No. 12/580,464, International Patent ApplicationPCT/US2009/005647, U.S. Patent Application 61/105,847, U.S. PatentApplication 61/152,631, and U.S. Patent Application 61/175,536 and U.S.Patent Application 61/441,251. In certain embodiments of the invention,the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate,solvate and polymorph thereof is administered every 12 or 24 hours at adaily dose of about 0.001 mg/kg to 5 mg/kg. In some embodiments, theSV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvateand polymorph thereof is administered every 12 or 24 hours at a dailydose of about 0.1 to 5 mg/kg, or about 1 to 2 mg/kg, or about 0.1 to 0.2mg/kg, or about 0.01 to 2.5 mg/kg, or about 0.1 to 2.5 mg/kg, or about0.4 to 2.5 mg/kg, or about 0.6 to 1.8 mg/kg, or about 0.04 to 2.5 mg/kg,or about 0.06 to 1.8 mg/kg, or about 0.01 to 1 mg/kg, or about 0.001 to1 mg/kg, or about 0.5 to 5 mg/kg, or about 0.05 to 0.5 mg/kg. In certainembodiments of the invention, the SV2A inhibitor or a pharmaceuticallyacceptable salt, hydrate, solvate or polymorph thereof is administeredevery 12 or 24 hours at a daily dose of about 0.001 to 5 mg/kg, about0.001 to 0.5 mg/kg, about 0.01 to 0.5 mg/kg, about 0.1 to 5 mg/kg, orabout 1 to 2 mg/kg, or about 2 to 4 mg/kg, or about 2 to 3 mg/kg, orabout 3 to 4 mg/kg, or about 0.2 to 0.4 mg/kg, or about 0.2 to 0.3mg/kg, or about 0.3 to 0.4 mg/kg, or about 0.1 to 0.2 mg/kg, or about0.01 to 2.5 mg/kg, or about 0.1 to 2.5 mg/kg, or about 0.4 to 2.5 mg/kg,or about 0.6 to 1.8 mg/kg, or about 0.5 to 2 mg/kg, or about 0.8 to 1.6,or about 0.8 to 3.6, or about 0.5 to 4 mg/kg, or about 0.04 to 2.5mg/kg, or about 0.06 to 1.8 mg/kg, or about 0.05 to 3 mg/kg or about0.08 to about 1.6 mg/kg, or about 0.08 to 3.6 or about 0.05 to 2 mg/kg,or about 0.01 to 1 mg/kg, or about 0.001 to 1 mg/kg, or about 0.5 to 5mg/kg, or about 0.05 to 0.5 mg/kg, or about 0.8 mg/kg, or about 1.6mg/kg, or about 3.6 mg/kg, or about 0.08 mg/kg, or about 0.16 mg/kg, orabout 0.36 mg/kg. Other doses higher than, intermediate to, or less thanthese doses may also be used and may be determined by one skilled in theart following the methods of this invention. For repeatedadministrations over several days or weeks or longer, depending on thecondition, the treatment is sustained until a sufficient level ofcognitive function is achieved.

In certain embodiments of the invention, the dose of the SV2A inhibitoris 0.001-5 mg/kg/day (which, given a typical human subject of 70 kg, isabout 0.07-350 mg/day). Doses that may be used include, but are notlimited to 0.001 mg/kg/day, 0.0015 mg/kg/day, 0.002 mg/kg/day, 0.005mg/kg/day, 0.0075 mg/kg/day, 0.01 mg/kg/day, 0.015 mg/kg/day, 0.02mg/kg/day, 0.03 mg/kg/day, 0.04 mg/kg/day, 0.05 mg/kg/day, 0.1mg/kg/day, 0.2 mg/kg/day, 0.3 mg/kg/day, 0.4 mg/kg/day, 0.5 mg/kg/day,0.75 mg/kg/day, 1.0 mg/kg/day, 1.5 mg/kg/day, 2.0 mg/kg/day, 2.5mg/kg/day, 3.0 mg/kg/day, 4.0 mg/kg/day, or 5.0 mg/kg/day. In someembodiments, the dose of the SV2A inhibitor is 0.001-0.5 mg/kg/day(which, given a typical human subject of 70 kg, is about 0.07-35mg/day), or 0.01-0.5 mg/kg/day (which is about 0.7-35 mg/day). Otherdoses higher than, intermediate to, or less than these doses may also beused and may be determined by one skilled in the art following themethods of this invention.

In certain embodiments of the invention, the dose of the SV2A inhibitoris 0.1 to 5 mg/kg/day (which, given a typical human subject of 70 kg, is7 to 350 mg/day). Doses that may be used include, but are not limited to0.1 mg/kg/day, 0.5 mg/kg/day, 1 mg/kg/day, 1.5 mg/kg/day, 2 mg/kg/day,2.5 mg/kg/day, 3 mg/kg/day, 4 mg/kg/day, or 5 mg/kg/day. In certainembodiments, the dose is 1-2 mg/kg/day (which, given a typical humansubject of 70 kg, is 70-140 mg/day). In other embodiments of theinvention, the dose of the SV2A inhibitor is 0.1 to 0.2 mg/kg/day. Otherdoses higher than, intermediate to, or less than these doses may also beused and may be determined by one skilled in the art following themethods of this invention.

In certain embodiments of the invention, the dose of the SV2A inhibitoris 0.01 to 2.5 mg/kg/day (which, given a typical human subject of 70 kg,is about 0.7-180 mg/day). Doses that may be used include, but are notlimited to 0.01 mg/kg/day, 0.02 mg/kg/day, 0.03 mg/kg/day, 0.04mg/kg/day, 0.06 mg/kg/day, 0.08 mg/kg/day, 0.12 mg/kg/day, 0.14mg/kg/day, 0.16 mg/kg/day, 0.18 mg/kg/day, 0.2 mg/kg/day, 0.4 mg/kg/day,0.6 mg/kg/day, 0.8 mg/kg/day, 1.0 mg/kg/day, 1.2 mg/kg/day, 1.4mg/kg/day, 1.6 mg/kg/day, 1.8 mg/kg/day, 2.0 mg/kg/day, 2.2 mg/kg/day,2.4 mg/kg/day, or 2.5 mg/kg/day. In some embodiments, the dose of theSV2A inhibitor is 0.1-2.5 mg/kg/day (which, given a typical humansubject of 70 kg, is about 7-180 mg/day), 0.1-0.2 mg/kg/day (which isabout 7-15 mg/day), 0.2-0.4 mg/kg/day (about 14-30 mg/day), 0.4-2.5mg/kg/day (about 25-180 mg/day), 0.6-1.8 mg/kg/day (about 40-130mg/day), 0.04-2.5 mg/kg/day (about 2.5-180 mg/day) or 0.06-1.8 mg/kg/day(about 4-130 mg/day). In some embodiments of the invention, the dose ofthe SV2A inhibitor is 40 to 130 mg, 140 to 300 mg, 200 to 300 mg or 140to 200 mg. Other doses higher than, intermediate to, or less than thesedoses may also be used and may be determined by one skilled in the artfollowing the methods of this invention.

In certain embodiments of the invention, the interval of administrationis 12 or 24 hours. Administration at less frequent intervals, such asonce every 6 hours, may also be used. In some embodiments, the SV2Ainhibitor is administered every 12 or 24 hours at a total daily dose of0.1 to 5 mg/kg (e.g., in the case of administration every 12 hours of adaily dose of 2 mg/kg, each administration is 1 mg/kg). In someembodiments, the SV2A inhibitor is administered every 24 hours at adaily dose of 1 to 2 mg/kg. In another embodiment, the SV2A inhibitor isadministered every 24 hours at a daily dose of 0.1-0.2 mg/kg. In someembodiments, the SV2A inhibitor is administered every 12 or 24 hours ata daily dose of 0.01 to 2.5 mg/kg (e.g., in the case of administrationevery 12 hours of a daily dose of 0.8 mg/kg, each administration is 0.4mg/kg). In some embodiments, the SV2A inhibitor is administered every 12or 24 hours at a daily dose of 0.1 to 2.5 mg/kg. In some embodiments,the SV2A inhibitor is administered every 12 or 24 hours at a daily doseof 0.4 to 2.5 mg/kg. In some embodiments, the SV2A inhibitor isadministered every 12 or 24 hours at a daily dose of 0.6 to 1.8 mg/kg.In some embodiments, the selective inhibitor of SV2A is administeredevery 12 or 24 hours at a daily dose of 0.04-2.5 mg/kg. In someembodiments, the selective inhibitor of SV2A is administered every 12 or24 hours at a daily dose of 0.06-1.8 mg/kg. In some embodiments, theselective inhibitor of SV2A is administered every 12 or 24 hours at adaily dose of 0.001-5 mg/kg. In some embodiments, the selectiveinhibitor of SV2A is administered every 12 or 24 hours at a daily doseof 0.001-0.5 mg/kg. In some embodiments, the selective inhibitor of SV2Ais administered every 12 or 24 hours at a daily dose of 0.01-0.5 mg/kg.

In certain embodiments of the invention, the SV2A inhibitor islevetiracetam or a pharmaceutically acceptable salt, hydrate, solvate orpolymorph thereof. The levetiracetam or its pharmaceutically acceptablesalt, hydrate, solvate or polymorph is administered every 12 or 24 hoursat a daily dose of about 1 to 2 mg/kg, or about 0.1 to 2.5 mg/kg, orabout 0.4 to 2.5 mg/kg, or about 0.6 to 1.8 mg/kg, or about 2.0 to 3.0mg/kg, or about 3.0 to 4.0 mg/kg, or about 2.0 to 4.0 mg/kg, or about0.1 to 5 mg/kg, or about 70 to 140 mg, or about 7 to 180 mg, or about 25to 180 mg, or about 40 to 130 mg, or about 140 to 300 mg, or about 200to 300 mg, or about 140 to 200 mg, or about 7 to 350 mg.

In other embodiments, the levetiracetam or its pharmaceuticallyacceptable salt, hydrate, solvate or polymorph is administered every 12or 24 hours according to one of the daily dose ranges indicated as “+”listed in Table 1 or Table 2.

TABLE 1 Daily Doses of Levetiracetam Lower range Upper 0.1 0.4 0.6 1 2 3range mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg 1.8 mg/kg  + + + + 2mg/kg + + + + 2.5 mg/kg  + + + + + 3 mg/kg + + + + + 4 mg/kg + + + + + +5 mg/kg + + + + + +

TABLE 2 Daily Doses of Levetiracetam in a Human Subject of 70 KG Lowerrange Upper 7 25 40 70 140 200 range mg mg mg mg mg mg 130 mg + + + +140 mg + + + + 180 mg + + + + + 200 mg + + + + + 300 mg + + + + + + 350mg + + + + + +

In certain embodiments of the invention, the SV2A inhibitor isbrivaracetam or a pharmaceutically acceptable salt, hydrate, solvate orpolymorph thereof. The brivaracetam or its pharmaceutically acceptablesalt, hydrate, solvate or polymorph thereof is administered every 12 or24 hours at a daily dose of about 0.1 to 0.2 mg/kg, or about 0.01 to 2.5mg/kg, or about 0.04 to 2.5 mg/kg, or about 0.06 to 1.8 mg/kg, or about0.2 to 0.4 mg/kg, or about 7 to 15 mg, or about 0.7 to 180 mg, or about2.5 to 180 mg, or about 4.0 to 130 mg, or about 14 to 30 mg.

In other embodiments, the brivaracetam or its pharmaceuticallyacceptable salt, hydrate, solvate or polymorph is administered every 12or 24 hours at a daily dose of at least 0.1 mg, 0.5 mg, 0.75 mg, 1.0 mg,1.5 mg, or 2.0 mg, but no more than a daily dose of 2.5 mg, 5 mg, 10 mg,15 mg, 20 mg, 25 mg, 30 mg, or 35 mg. In other embodiments, thebrivaracetam or its pharmaceutically acceptable salt, hydrate, solvateor polymorph is administered every 12 or 24 hours at a daily dose of atleast 0.0015 mg/kg, 0.0075 mg/kg, 0.01 mg/kg, 0.015 mg/kg, 0.02 mg/kg,or 0.03 mg/kg, but no more than a daily dose of 0.5 mg/kg, 0.4 mg/kg,0.3 mg/kg, 0.2 mg/kg, 0.15 mg/kg, 0.1 mg/kg, 0.05 mg/kg, or 0.04 mg/kg.

In other embodiments, the brivaracetam or its pharmaceuticallyacceptable salt, hydrate, solvate or polymorph is administered every 12or 24 hours according to one of the daily dose ranges indicated as “+”listed in Table 3 or Table 4. For example, the brivaracetam or apharmaceutically acceptable salt, hydrate, solvate or polymorph thereofmay be administered every 12 or 24 hours at a daily dose of 0.1-35 mg,0.5-35 mg, 0.75-35 mg, 1.0-35 mg, 1.5-35 mg, 2.0-35 mg, 0.1-30 mg,0.1-25 mg, 0.1-20 mg, 0.1-15 mg, 0.1-10 mg, 0.1-5 mg, 0.1-2.5 mg,0.0015-0.5 mg/kg, 0.0075-0.5 mg/kg, 0.01-0.5 mg/kg, 0.015-0.5 mg/kg,0.02-0.5 mg/kg, 0.03-0.5 mg/kg, 0.0015-0.4 mg/kg, 0.0015-0.3 mg/kg,0.0015-0.2 mg/kg, 0.0015-0.15 mg/kg, 0.0015-0.1 mg/kg, 0.0015-0.05mg/kg, or 0.0015-0.04 mg/kg.

TABLE 3 Daily Doses of Brivaracetam Lower range Upper 0.0015 0.0075 0.010.015 0.02 0.03 range mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg 0.04mg/kg  + + + + + + 0.05 mg/kg  + + + + + + 0.1 mg/kg + + + + + + 0.15mg/kg  + + + + + + 0.2 mg/kg + + + + + + 0.3 mg/kg + + + + + + 0.4mg/kg + + + + + + 0.5 mg/kg + + + + + +

TABLE 4 Daily Doses of Brivaracetam in a Human Subject of 70 KG Lowerrange Upper 0.1 0.5 0.75 1.0 1.5 2.0 range mg mg mg mg mg mg 2.5mg  + + + + + +  5 mg + + + + + + 10 mg + + + + + + 15 mg + + + + + + 20mg + + + + + + 25 mg + + + + + + 30 mg + + + + + + 35 mg + + + + + +

In certain embodiments of the invention, the SV2A inhibitor isseletracetam or a pharmaceutically acceptable salt, hydrate, solvate orpolymorph thereof. In some embodiments, the seletracetam or itspharmaceutically acceptable salt, hydrate, solvate or polymorph thereofis administered every 12 or 24 hours at a daily dose of at least 0.1 mg,0.5 mg, 0.75 mg, 1.0 mg, 1.5 mg, or 2.0 mg, but no more than a dailydose of 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 35 mg. Inother embodiments, the seletracetam or a pharmaceutically acceptablesalt, hydrate, solvate or polymorph thereof is administered every 12 or24 hours at a daily dose of at least 0.0015 mg/kg, 0.0075 mg/kg, 0.01mg/kg, 0.015 mg/kg, 0.02 mg/kg, or 0.03 mg/kg, but no more than a dailydose of 0.5 mg/kg, 0.4 mg/kg, 0.3 mg/kg, 0.2 mg/kg, 0.15 mg/kg, 0.1mg/kg, 0.05 mg/kg, or 0.04 mg/kg.

In certain embodiments of the invention, the seletracetam or itspharmaceutically acceptable salt, hydrate, solvate or polymorph isadministered according to one of the daily dose ranges indicated as “+”listed in Table 5 or Table 6. For example, the seletracetam or itspharmaceutically acceptable salt, hydrate, solvate or polymorph may beadministered every 12 or 24 hours at a daily dose of 0.1-35 mg, 0.5-35mg, 0.75-35 mg, 1.0-35 mg, 1.5-35 mg, 2.0-35 mg, 0.1-30 mg, 0.1-25 mg,0.1-20 mg, 0.1-15 mg, 0.1-10 mg, 0.1-5 mg, 0.1-2.5 mg, 0.0015-0.5 mg/kg,0.0075-0.5 mg/kg, 0.01-0.5 mg/kg, 0.015-0.5 mg/kg, 0.02-0.5 mg/kg,0.03-0.5 mg/kg, 0.0015-0.4 mg/kg, 0.0015-0.3 mg/kg, 0.0015-0.2 mg/kg,0.0015-0.15 mg/kg, 0.0015-0.1 mg/kg, 0.0015-0.05 mg/kg, or 0.0015-0.04mg/kg.

TABLE 5 Daily Doses of Seletracetam Lower range Upper 0.0015 0.0075 0.010.015 0.02 0.03 range mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg 0.04mg/kg  + + + + + + 0.05 mg/kg  + + + + + + 0.1 mg/kg + + + + + + 0.15mg/kg  + + + + + + 0.2 mg/kg + + + + + + 0.3 mg/kg + + + + + + 0.4mg/kg + + + + + + 0.5 mg/kg + + + + + +

TABLE 6 Daily Doses of Seletracetam in a Human Subject of 70 KG Lowerrange Upper 0.1 0.5 0.75 1.0 1.5 2.0 range mg mg mg mg mg mg 2.5mg  + + + + + +  5 mg + + + + + + 10 mg + + + + + + 15 mg + + + + + + 20mg + + + + + + 25 mg + + + + + + 30 mg + + + + + + 35 mg + + + + + +

In certain embodiments of the invention, the seletracetam or itspharmaceutically acceptable salt, hydrate, solvate or polymorph isadministered according to one of the daily dose ranges indicated abovefor levetiracetam.

In some embodiments, the antipsychotic useful in the present inventionis an atypical antipsychotic. Generally the amount of an atypicalantipsychotic administered to a patient is an amount sufficient to havea therapeutic effect. In a preferred embodiment the amount of anatypical antipsychotic administered to a patient is an amount sufficientto treat at least one symptom or sign of schizophrenia or bipolardisorder (in particular, mania), wherein the one sign or symptom mayinclude, but are not limited to, any of those described above,including, for example, delusions, hallucinations, disorganized speech(e.g., frequent derailment or incoherence), grossly disorganized orcatatonic behavior and negative symptoms (e.g., affective flattening,alogia, avolition). One skilled in the art will recognize that theamount of atypical antipsychotic will vary with many factors includingthe potency of the atypical antipsychotic, the age and weight of thepatient, and the severity of the condition or disorder to be treated.The dosages of the drugs used in the present invention can, in the finalanalysis, be set by the physician in charge of the case, using knowledgeof the drugs, the properties of the drugs in combination as determinedin clinical trials, and the characteristics of the patient, includingdiseases other than that for which the physician is treating thepatient.

Non-limiting daily dosage amounts for several atypical antipsychoticsare provided herein:

Aripiprazole, about 0.1-150 mg/day, about 1-150 mg/day, about 1-100mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, andin some embodiments, up to about 30 mg/day or about 10-15 mg/day;Asenapine, about 0.1-150 mg/day, about 1-150 mg/day, about 1-100 mg/day,about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, and in someembodiments, about 10 mg/day;Clozapine, about 0.1-1000 mg/day, about 1-900 mg/day, about 5-900mg/day, about 10-900 mg/day, about 100-900 mg/day, about 100-800 mg/dayor about 100-750 mg/day, and in some embodiments, about 150-450 mg/dayor about 300-450 mg/day;Iloperidone, about 0.1-150 mg/day, about 1-150 mg/day, about 1-100mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, andin some embodiments, about 12-24 mg/day;Olanzapine, about 0.1-150 mg/day, about 1-150 mg/day, about 1-100mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, andin some embodiments, about 10-15 mg/day;Lurasidone, about 0.1-500 mg/day, about 1-500 mg/day, about 1-250mg/day, about 10-250 mg/day, about 10-100 mg/day, or about 20-100mg/day, and in some embodiments, about 40-80 mg/day;Paliperidone, about 0.1-150 mg/day, about 1-150 mg/day, about 1-100mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, andin some embodiments, about 6 mg/day;Quetiapine, about 0.1-1000 mg/day, about 1-900 mg/day, about 1-800mg/day, about 50-800, about 100-800, or about 200-800 mg/day, and insome embodiments, about 150-750 mg/day, about 300 mg/day or about400-800 mg/day;Risperidone, about 0.1-150 mg/day, about 1-150 mg/day, about 1-100mg/day, about 1-80 mg/day, about 1-50 mg/day, or about 5-50 mg/day, andin some embodiments, about 4-8 mg/day or 1-6 mg/day;Ziprasidone, about 0.1-250 mg/day, about 1-150 mg/day, about 1-100mg/day, about 20-100, or about 20-80 mg/day, and in some embodiments, upto about 40 mg/day, or up to about 80 mg/day or about 40-80 mg/day.

For repeated administrations over several days or weeks or longer,depending on the condition, the treatment is sustained until asufficient level of cognitive function is achieved.

The antipsychotic or a salt, hydrate, solvate or polymorph thereof maybe administered at dosage levels distinct from conventional levels(e.g., at subtherapeutic doses) when provided in combination with SV2Ainhibitor, due to a SV2A inhibitor-dependent increase in theantipsychotic's therapeutic index. In some embodiments, the increase inthe antipsychotic's therapeutic index due to the combination with SV2Ainhibitor is greater than the therapeutic index of the antipsychoticadministered in the absence of a SV2A inhibitor by at least about 1.5×or 2.0× or 2.5× or 3.0× or 3.5× or 4.0× or 4.5× or 5.0× or 5.5× or 6.0×or 6.5× or 7.0× or 7.5× or 8.0× or 8.5× or 9.0× or 9.5× or 10×, orgreater than about 10×. In some embodiments, combination of anantipsychotic with the SV2A inhibitor reduces the dosage of theantipsychotic required for its therapeutic effect. In some embodiments,the antipsychotic is an atypical antipsychotic. When used in combinationwith SV2A inhibitor, such atypical antipsychotic is administered at adose lower than required for its therapeutic effect when administered inthe absence of SV2A inhibitor.

The frequency of administration of the composition of this invention maybe adjusted over the course of the treatment, based on the judgment ofthe administering physician. It will be clear that the SV2A inhibitorand the antipsychotic and their salts, hydrates, solvates and polymorphscan be administered at different dosing frequencies or intervals. Forexample, SV2A inhibitor can be administered daily (including multipledoses per day) or less frequently. An antipsychotic can be administereddaily (including multiple doses per day) or less frequently. In someembodiments, sustained continuous release formulations of a SV2Ainhibitor and an antipsychotic may be desired. Various formulations anddevices for achieving sustained release are known in the art.

The use of a combination of an SV2A inhibitor and an antipsychotic mayreduce the amount of the antipsychotic necessary for treatment ofschizophrenia or bipolar disorder (in particular, mania), and may thusreduce the side effects caused by the antipsychotics. In particular, thecombination of an SV2A inhibitor with a reduced amount of antipsychoticmay reduce the side effects without negatively impacting efficacy.Accordingly, in some embodiments, a subtherapeutic amount ofantipsychotic is administered.

In some embodiments, a suitable amount of the SV2A inhibitor isadministered so as to reduce the dose of the antipsychotic by at leastabout 20%, at least about 30%, at least about 40%, or at least about50%, at least about 60%, at least about 70%, at least about 80%, atleast about 90% or more from to the dose of the antipsychotic normallyused when administered alone (i.e., individually and not in combinationwith other therapeutic agents or compounds). The reduction may bereflected in terms of amount administered at a given administrationand/or amount administered over a given period of time (reducedfrequency).

In certain embodiments of the invention, the combined administration ofSV2A inhibitor or a salt, hydrate, solvate and polymorph thereof and anantipsychotic or a salt, hydrate, solvate and polymorph thereof canattain a longer or improved therapeutic effect in the subject than thatattained by administering only the SV2A inhibitor or only theantipsychotic, by at least about 1.5×, or 2.0×, or 2.5×, or 3.0×, or3.5×, or 4.0×, or 4.5×, or 5.0×, or 5.5×, or 6.0×, or 6.5×, or 7.0×, or7.5×, or 8.0×, or 8.5×, or 9.0×, or 9.5×, or 10×, or greater than about10×.

Compositions of this Invention

In one aspect, the invention provides compositions comprising a SV2Ainhibitor and at least one antipsychotic and their salts, hydrates,solvates and polymorphs. In some embodiments, the SV2A inhibitor and theantipsychotic may be present in a single dosage unit (e.g., combinedtogether in one capsule, tablet, powder, or liquid, etc.).

The SV2A inhibitor and the antipsychotic suitable for the compositionsof this invention may be selected from any of those as described above.In some embodiments, the SV2A inhibitor is selected from any of thosedescribed above; and the antipsychotic is selected from (1) atypical andtypical antipsychotics (such as those described above); (2) agents thatare dopaminergic agents (such as dopamine D1 receptor antagonists oragonists, dopamine D₂ receptor antagonists or partial agonists, dopamineD3 receptor antagonists or partial agonists, dopamine D4 receptorantagonists), glutamatergic agents, NMDA receptor positive allostericmodulators, glycine reuptake inhibitors, glutamate reuptake inhibitor,metabotropic glutamate receptors (mGluRs) agonists or positiveallosteric modulators (PAMs) (e.g., mGluR2/3 agonists or PAMs),glutamate receptor glur5 positive allosteric modulators (PAMs), M1muscarinic acetylcholine receptor (mAChR) positive allosteric modulators(PAMs), histamine H3 receptor antagonists, AMPA/kainate receptorantagonists, ampakines (CX-516), glutathione prodrugs, noradrenergicagents (such as alpha-2 adrenergic receptor agonists or antagonists andCOMT inhibitors), serotonin receptor modulators (such as 5-HT_(2A)receptor antagonists, 5-HT_(1A) receptor partial agonists, 5-HT_(2c)agonists, and 5-HT6 antagonists), cholinergic agents (such as alpha-7nicotinic receptor agonists, alpha4-beta2 nicotinic receptor agonists,allosteric modulators of nicotinic receptors and acetylcholinesteraseinhibitors, muscarinic receptor agonists and antagonists), cannabinoidCB1 antagonists, neurokinin 3 antagonists, neurotensin agonists, MAO Binhibitors, PDE10 inhibitors, nNOS inhibits, neurosteroids, andneurotrophic factors, including, e.g., those specific such agentsdescribed above, and (3) any compounds that are useful in treating oneor more sign or symptoms of schizophrenia or bipolar disorder (inparticular, mania) (including, e.g., the agents disclosed in any of theabove-listed patents or patent application publications), andpharmaceutically acceptable salts, hydrates, solvates, polymorphs orprodrugs thereof. In some embodiments, the SV2A inhibitor is selectedfrom the group consisting of levetiracetam, seletracetam, andbrivaracetam or derivatives or analogs or pharmaceutically acceptablesalts, or solvates, or hydrates, or polymorphs, or prodrugs thereof; andthe antipsychotic is an atyptical antipsychotic selected from, e.g.,aripiprazole, olanzapine and ziprasidone, and pharmaceuticallyacceptable salts, hydrates, solvates, polymorphs or prodrugs thereof. Insome embodiments, the SV2A inhibitor is selected from levetiracetam orderivatives or analogs or pharmaceutically acceptable salts, orsolvates, or hydrates, or polymorphs, or prodrugs thereof; and theantipsychotic is an atyptical antipsychotic selected from, e.g.,aripiprazole, olanzapine and ziprasidone, and pharmaceuticallyacceptable salts, hydrates, solvates, polymorphs or prodrugs thereof.

The composition described herein can contain more than one SV2Ainhibitor and/or more than one antipsychotic. In some embodiments, theSV2A inhibitor and the antipsychotic are in a single dosage form, in aunit dosage form, in separate dosage forms, or in separate dosage formspackaged together.

The compositions described herein can further contain pharmaceuticallyacceptable excipient(s) and may contain other agents that serve toenhance and/or complement the effectiveness of the SV2A inhibitor and/orthe antipsychotic. The compositions may also contain additional agentsknown to be useful for treating cognitive function disorder.

The composition in the present invention may be in solid dosage formssuch as capsules, tablets, dragrees, pills, lozenges, powders andgranule. Where appropriate, they may be prepared with coatings such asenteric coatings or they may be formulated so as to provide controlledreleases of one or more active ingredient such as sustained or prolongedrelease according to methods well known in the art. In certainembodiments, the composition is in form of a slow, controlled, orextended release. The term “extended release” is widely recognized inthe art of pharmaceutical sciences and is used herein to refer to acontrolled release of an active compound or agent from a dosage form toan environment over (throughout or during) an extended period of time,e.g. greater than or equal to one hour. An extended release dosage formwill release drug at substantially constant rate over an extended periodof time or a substantially constant amount of drug will be releasedincrementally over an extended period of time. The term “extendedrelease” used herein includes the terms “controlled release”, “prolongedrelease”, “sustained release”, or “slow release”, as these terms areused in the pharmaceutical sciences. In some embodiments, the extendedrelease dosage is administered in the form of a patch or a pump. Thecomposition may also be in liquid dosage forms including solutions,emulsions, suspensions, syrups, and elixirs.

The compositions may be specifically formulated for administration byany suitable route as described herein and known in the art.Compositions for parental administration include sterile aqueous andnonaqueous injectable solutions, dispersions, suspensions or emulsionsas well as sterile powders to be reconstituted in sterile injectablesolutions or dispersions prior to use. Compositions for intraoral andoral delivery (including sublingual and buccal administration, e.g.Danckwerts et al, and oral) include but are not limited to bioadhesivepolymers, tablets, patches, liquids and semisolids (see e.g., Smart etal). Compositions for respiratory delivery (pulmonary and nasaldelivery) include but are not limited to a variety of pressurizedmetered dose inhalers, dry powder inhalers, nebulizers, aqueous mistinhalers, drops, solutions, suspensions, sprays, powders, gels,ointments, and specialized systems such as liposomes and microspheres(see e.g. Owens et al, “Alternative Routes of Insulin Delivery” andMartini et al). Compositions for transdermal delivery include but arenot limited to colloids, patches, and microemulsions. Other suitableadministration forms for the above and other include depot injectableformulations, suppositories, sprays, ointments, cremes, gels, inhalants,dermal patches, implants etc.

The compositions may also contain adjuvants, such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents which delay absorption, such as aluminum monostearate andgelatin.

Therapeutic formulations can be prepared by methods well known in theart of pharmacy, see, e.g., Goodman et al., 2001; Ansel, et al., 2004;Stoklosa et al., 2001; and Bustamante, et al., 1993.

In certain embodiments of the invention, a composition containing anSV2A inhibitor and an antipsychotic and their salts, hydrates, solvatesand polymorphs comprises an amount of the SV2A inhibitor between 0.07and 350 mg, or between 50 and 200 mg, or between 3 and 50 mg. In someembodiments, the amount of the SV2A inhibitor is less than 350 mg, lessthan 250 mg, less than 200 mg, less than 150 mg, less than 100 mg, lessthan 50 mg, less than 10 mg, less than 5 mg, less than 1 mg, less than0.5 mg, less than 0.1 mg, or less than 0.07 mg. In certain embodimentsof the invention, a composition containing an SV2A inhibitor or itspharmaceutically acceptable salt, hydrate, solvate or polymorphcomprises the SV2A inhibitor in an amount of 0.07-60 mg, 0.07-350 mg,25-60 mg, 25-125 mg, 50-250 mg, 5 140 mg, 0.7-180 mg, 125-240 mg, 3-50mg, or 3-60 mg. In some embodiments, a composition containing an SV2Ainhibitor or its pharmaceutically acceptable salt, hydrate, solvate orpolymorph comprises the SV2A inhibitor in an amount of 0.05-35 mg. Insome embodiments of the composition of the present invention, the SV2Ainhibitor may be selected from the group consisting of levetiracetam,brivaracetam, and seletracetam or derivatives or analogs orpharmaceutically acceptable salts, hydrates, solvates, or polymorphsthereof, said SV2A inhibitor being present in an amount selected fromany of the above.

It will be understood by one of ordinary skill in the art that thecompositions and methods described herein may be adapted and modified asis appropriate for the application being addressed and that thecompositions and methods described herein may be employed in othersuitable applications, and that such other additions and modificationswill not depart from the scope hereof

This invention will be better understood from the Experimental Detailswhich follow. However, one skilled in the art will readily appreciatethat the specific methods and results discussed are merely illustrativeof the invention as described more fully in the embodiments which followthereafter.

EXAMPLES

Introduction and Models of Cognitive Impairment

A variety of conditions characterized by cognitive impairment, e.g.,Age-Associated Memory Impairment (AAMI), Mild Cognitive Impairment (MCI)and Age-related Cognitive Decline (ARCD) are believed to be related toaging. Others are related to disease, for example, AD. Animal modelsserve as an important resource for developing and evaluating treatmentsfor such age-related cognitive impairments. Features that characterizeage-related cognitive impairment in animal models typically extend toage-related cognitive impairment in humans. Efficacy in such animalmodels is, thus, predictive of efficacy in humans.

Of available models, a Long-Evans rat model of cognitive impairment isparticularly well suited for distinguishing the difference betweencognitive impairment related to illness and that related to aging.Indeed, extensive behavioral characterization has identified a naturallyoccurring form of cognitive impairment in an outbred strain of agedLong-Evans rats (Charles River Laboratories; Gallagher et al., Behav.Neurosci. 107:618-626, (1993)). In a behavioral assessment with theMorris Water Maze (MWM), rats learn and remember the location of anescape platform guided by a configuration of spatial cues surroundingthe maze. The cognitive basis of performance is tested in probe trialsusing measures of the animal's spatial bias in searching for thelocation of the escape platform. Aged rats in the study population haveno difficulty swimming to a visible platform, but an age-dependentimpairment is detected when the platform is camouflaged, requiring theuse of spatial information. Performance for individual aged rats in theoutbred Long-Evans strain varies greatly. For example, a proportion ofthose rats perform on a par with young adults. However, approximately40-50% fall outside the range of young performance. This variabilityamong aged rats reflects reliable individual differences. Thus, withinthe aged population some animals are cognitively impaired and designatedaged-impaired (AI) and other animals are not impaired and are designatedaged-unimpaired (AU). See, e.g., Colombo et al., Proc. Natl. Acad. Sci.94: 14195-14199, (1997); Gallagher and Burwell, Neurobiol. Aging 10:691-708, (1989); Rapp and Gallagher, Proc. Natl. Acad. Sci. 93:9926-9930, (1996); Nicolle et al., Neuroscience 74: 741-756, (1996); andNicolle et al., J. Neurosci. 19: 9604-9610, (1999).

We used the above-described rat model to identify individual AI and AUrats. We then conducted behavioral assessment on AI rats whileadministering various pharmacological treatments.

Example 1: Increased Gene Expression of SV2A in Aged-Impaired RatsBehavioral Characterization of Young, Aged-Impaired and Aged-UnimpairedRats in Morris Water Maze (MWM)

Behavioral tests were performed on young (4 months old) and aged (24months old) pathogen-free male Long-Evans rats.

The MWM apparatus consists of a large, circular pool (diameter 1.83 m;height, 0.58 m) filled with water (27° C.) that is made opaque throughthe addition of non-toxic pigment or some other substance. In thetypical “hidden platform” version of the test, rats are trained to finda camouflaged white escape platform (height, 34.5 cm) that is positionedin the center of one quadrant of the maze about 1.0 cm below the watersurface. This platform can be retracted to the bottom of the tank orraised to its normal position from outside the maze during behavioraltesting. The location of the platform remains constant from trial totrial. Because there are no local cues that mark the position of theplatform, the rat's ability to locate it efficiently from any startingposition at the perimeter of the pool depends on using informationsurrounding the maze. The maze is surrounded by black curtains to whichwhite patterns are affixed to provide a configuration of spatial cues. Asecond platform (height 37.5 cm), with its surface painted black iselevated 2 cm above the water surface during cue training to control forfactors unrelated to cognition. The behavior of a rat in the pool isrecorded by a camera that is suspended 2.5 m above the center of thepool. The camera is connected to a video tracking system (HVS ImageAdvanced Tracker VP200) and a PC computer running HVS software developedby Richard Baker of HVS Image, Hampton, UK.

The MWM protocol is optimized for sensitivity to the effects of aging oncognition and for measures of reliable individual differences within theaged population of out-bred Long-Evans rats (Gallagher et al. Behav.Neurosci. 107:618-626, (1993)). Rats receive three trials per day for 8consecutive days, using a 60 sec inter-trial interval. On each trainingtrial, the rat is released into the maze from one of four equally spacedstarting positions around the perimeter of the pool. The startingposition varies from trial to trial, thus preventing the use of aresponse strategy (e.g., always turning left from the start location tolocate the escape platform). If a rat does not locate the escapeplatform within 90 sec on any trial, the experimenter guides the rat tothe platform, where it remains for 30 sec. Every sixth trial consists ofa probe trial to assess the development of spatial bias in the maze.During these trials, the rat swims with the platform retracted to thebottom of the pool for 30 sec, at which time the platform is raised toits normal position for completion of the escape trial. At thecompletion of the protocol using the hidden platform, rats are assessedfor cue learning using the visible platform. The location of thisplatform varies from trial to trial in a single session of 6 trainingtrials.

The proximity of the animal's position with respect to the goal is usedto analyze the training trial and probe trial performance. The proximitymeasure is obtained by sampling the position of the animal in the maze(10 times/sec) to provide a record of distance from the escape platformin 1 sec averages. For both probe trials and training trials, acorrection procedure is implemented so that trial performance isrelatively unbiased by differences in distance to the goal from thevarious start locations at the perimeter of the pool. In making thiscorrection, the average swimming speed is calculated for each trial(path length/latency). Then, the amount of time required to swim to thegoal at that speed from the start location used for the trial is removedfrom the record prior to computing trial performance, i.e., cumulativedistance on training trials and average distance from the goal on probetrials. Thus, scores obtained using the proximity measure are designedto reflect search error, representing deviations from an optimal search,i.e. direct path to the goal and search in the immediate vicinity ofthat location during probe trials.

Computer records of video-tracking are compiled to provide data on eachrat's performance in the maze. Measures on training trials and probetrials are analyzed by Analysis of Variance (ANOVA).

In one set of trials, the performance during training with the hidden,camouflaged platform differs between the groups of young and aged rats[F (1, 23)=12.69, p<0.002]. In this set of trials, no difference betweenthe groups is observed for the cue training trials with a visibleplatform. In this set of trials, latencies to escape during cue trainingaveraged 9.36 seconds for young and 10.60 seconds for the aged rats.

An average proximity measure on interpolated probe trials is used tocalculate a spatial learning index for each individual subject asdescribed in detail in Gallagher et al., Behav. Neurosci. 107:618-26,(1993). When a rat rapidly learns to search for the platform close toits position, its spatial learning index is low. Overall, in one set oftrials aged rats differed from young rats [F (1, 23)=15.18, p<0.001].Aged rats are classified as either unimpaired or impaired relative tothe learning index profile of the young study population. Aged rats thatfall within the normative range of young rats (index scores<241) aredesignated aged-unimpaired (AU). The remaining aged subjects that haveindex scores outside the range of young performance are designatedaged-impaired (AI).

Preparation of RNA from Behaviorally Characterized Rats

Twenty-four outbred Long-Evans rats, behaviorally characterized as isdescribed above, are killed by live decapitation to obtain fresh braintissue. The brain is removed, and the dentate gyrus hippocampal regionis microdissected from 500 micron sections taken through the transverseaxis of the entire hippocampal formation (both left and righthippocampi) of 24 characterized rats. There are 8 animals in each group(AI, AU, and Y).

Total RNA is isolated using Trizol reagent (Invitrogen, Carlsbad,Calif.) according to the standard protocol (homogenization in Trizolreagent followed by chloroform extraction and isopropanolprecipitation). Total RNA is further purified using the RNeasy mini kit(Qiagen, Valencia, Calif.). cRNA probes are then generated from the RNAsamples at the Johns Hopkins Microarray Core Facility, generallyaccording to Affymetrix specifications.

Briefly, 5 μg of total RNA is used to synthesize first strand cDNA usingoligonucleotide probes with 24 oligo-dT plus T7 promoter as primer(Proligo LLC, Boulder, Calif.), and the SuperScript Choice System(Invitrogen). Following the double stranded cDNA synthesis, the productis purified by phenol-chloroform extraction, and biotinilated anti-sensecRNA is generated through in vitro transcription using the BioArray RNAHigh Yield Transcript Labeling kit (ENZO Life Sciences Inc.,Farmingdale, N.Y.). 15 μg of the biotinilated cRNA is fragmented at 94°C. for 35 min (100 mM Trix-acetate, pH 8.2, 500 mM KOAC, 150 mM MgOAC).10 μg of total fragmented cRNA is hybridized to the RAT genome 230-2Affymetrix GeneChip array for 16 hours at 45° C. with constant rotation(60 rpm).

Affymetrix Fluidics Station 450 is then used to wash and stain thechips, removing the non-hybridized target and incubating with astreptavidin-phycoerythrin conjugate to stain the biotinilated cRNA. Thestaining is then amplified using goat immunoglobulin-G (IgG) as blockingreagent and biotinilated anti-streptavidin antibody (goat), followed bya second staining step with a streptavidin-phycoerythrin conjugate.

For quality control of the total RNA from the samples, the AgilentBioanalyzer, Lab on a Chip technology, is used to confirm that all thesamples had optimal rRNA ratios (1:2, for 18S and 28S, respectively) andclean run patterns.

For quality control of the hybridization, chip image, and comparisonbetween chips, the following parameters are considered: Scaling factor:related to the overall intensity of the chip, to confirm the similarsignal intensity and staining through out the samples; Background:estimation of unspecific or cross-hybridization; Percentage of presentcalls: percentage of transcripts that are considered significantlyhybridized to the chip (present) by the algorithm;Glyseraldehyde-3-phosphate dehydrogenase (GAPDH) (3′/5′): representationof the RNA integrity by measuring the ratio of 3′ to 5′ regions for thehousekeeping gene GAPDH, its presence in the chip and a ratio close to 1advocates for a good integrity of the target (sample); Spikes(BioB/BioC) to confirm the detection level and sensitivity afterhybridization.

Data Analysis of Microarray

Fluorescence is detected using the Affymetrix G3000 GeneArray Scannerand image analysis of each GeneChip is done through the GeneChipOperating System 1.1.1 (GCOS) software from Affymetrix, using thestandard default settings. All of the GeneChip arrays use shortoligonucleotides for genes in an RNA sample.

For comparison between different chips, global scaling is used, scalingall probe sets to target intensity (TGT) of 150. Total number of presentcalls and scaling factors are similar across all chips. Further analysisfor presence/absence and statistical difference is performed on a regionby region basis in the following manner. Probe sets are determined to bepresent in a region if it had a present call in four of eight animals ina single group.

Probe sets are annotated using the Affymetrix annotation of Jun. 20,2005, and all probe sets representing a specific gene are identified.

An ANOVA is conducted on the probe set signal values for all presentprobe sets by combining two groups of animals and comparing them to thethird group. An “AI ANOVA” is performed, where AU group are combinedwith Young group and compared to AI group.

Pearsons's correlations comparing probe set signal values to learningindices were calculated for the aged animals (excluding young) acrossall present probe sets. As shown in FIG. 1, expression of genes encodingSV2A was significantly increased in aged-impaired (AI) individualsrelative to young individuals (Y) and aged-unimpaired individuals (AU)in a set of experiments performed as above. These results show thatincreased SV2A expression was correlated to the development ofage-related cognitive impairment.

Example 2: Effect of Levetiracetam in Aged-Impaired Rats Morris WaterMaze Results

Six Age-Impaired (AI) Long-Evans rats (as characterized above) weretested for their memory of new spatial information in the MWM, underdifferent drug/control treatment conditions (vehicle control and twodifferent dosage levels of levetiracetam). The MWM protocol wassubstantially the same as the one described in Example 1. Specificallyfor this study, a retention trial was performed after the trainingtrials, as described below.

AI rats were given six training trials per training day with a 60-secinter-trial interval between each training trial for two consecutivedays. On each training trial, the rat was released in the maze from oneof four equally spaced starting positions around the perimeter of thepool. If the rat did not locate the escape platform within 90 sec on anytrial, the experimenter guided the rat to the platform, where itremained for 30 sec. 30 minutes to 1 hour prior to all the trainingtrials on each training day, AI rats were pretreated with one of threedrug conditions: 1) vehicle control (0.9% saline solution); 2)levetiracetam (5 m/kg/day); and 3) levetiracetam (10 mg/kg/day); throughintraperitoneal (i.p.) injection. The same six AI rats were used for theentire trials so that each treatment condition was tested on all sixrats. Therefore, to counterbalance any potential bias, both the locationof the escape platform and the spatial cues surrounding the water mazewere different in the three treatment conditions. Therefore, using oneset of locations and spatial cues, two rats were treated with salinecontrol solution, two with levetiracetam (5 m/kg/day) and two withlevetiracetam (10 mg/kg/day). Using the second set of locations andspatial cues, the two rats treated with saline control solution in thefirst test were treated with either levetiracetam (5 m/kg/day) orlevetiracetam (10 mg/kg/day), and the two rats previously treated withlevetiracetam (5 m/kg/day) were treated with either saline controlsolution or levetiracetam (10 mg/kg/day), and the two rats previouslytreated with levetiracetam (10 mg/kg/day) were treated with eithersaline control solution or levetiracetam (5 m/kg/day). Using the lastset of locations and spatial cues, the rat groupings were again switchedso that each group was treated with a different condition than they hadbeen treated previously.

After the second training day and completion of the twelve trainingtrials (over the two days), the rat was returned to its home cage andplaced in the animal housing room. After a delay of 24 hours from thelast training trial, the rat was given one testing trial (the “retentiontrial”), which was the same MWM task as the training trials, but withthe escape platform removed.

For the retention trial, the MWM circular pool was divided into 4quadrants. The particular quadrant where the escape platform was placedin the training trials is referred as “target quadrant”. The particularregion where the platform was located in the training trials is referredas “target annulus”. In the retention trial, the time the AI rats spentswimming in the target quadrant is measured and further plotted as apercentage of total swimming time. FIG. 2 displays the results of onesuch set of retention trials. The time the AI rats spend in the targetannulus is also measured. FIG. 2 displays the results of one such set ofretention trials. Time data are collected for all three drug treatmentconditions.

In the retention trial, whose results are depicted in FIG. 2, the timethe AI rats spent in the target quadrant was approximately 25%, which isa performance equivalent to them having no memory of the platformlocation. This performance did not significantly improve in the grouptreated with levetiractam at 5 mg/kg/day. However, the group treatedwith levetiractam at 10 mg/kg/day demonstrated significantly improvedmemory as compared to vehicle-treated controls, as indicated by asignificant increase in the time spent in the target quadrant toapproximately 35% of total swimming time (see FIG. 2). That level ofperformance is equivalent to young and age-unimpaired rats, indicatingthat treatment with 10 mg/kg/day levetiractam resulted in a significantrecovery of the AI rats' ability to navigate this MWM. The effectivenessof the 10 mg/kg/day levetiracetam treatment was also seen in the timespent in the target annulus (see FIG. 2).

Radial Arm Maze Results

The effects of levetiracetam on the spatial memory retention ofaged-impaired (AI) rats were assessed in a Radial Arm Maze (RAM)behavioral task using vehicle control and five different dosage levelsof levetiracetam (1.25 mg/kg/day, 2.5 mg/kg/day, 5 mg/kg/day, 10mg/kg/day and 20 mg/kg/day). RAM behavioral tasks were preformed on tenAI rats. All six treatment conditions were tested on all ten rats, asdescribed above for the MWM test.

The RAM apparatus used consisted of eight equidistantly-spaced arms. Anelevated maze arm (7 cm width×75 cm length) projected from each facet ofan octagonal center platform (30 cm diameter, 51.5 cm height). Clearside walls on the arms were 10 cm high and were angled at 65° to form atrough. A food well (4 cm diameter, 2 cm deep) was located at the distalend of each arm. Froot Loops™ (Kellogg Company) were used as rewards.Blocks constructed of Plexiglas™ (30 cm height×12 cm width) could bepositioned to prevent entry to any arm. Numerous extra maze cuessurrounding the apparatus were also provided.

The AI rats were initially subjected to a pre-training test (Chappell etal. Neuropharmacology 37: 481-487, 1998). The pre-training testconsisted of a habituation phase (4 days), a training phase on thestandard win-shift task (18 days) and another training phase (14 days)in which a brief delay was imposed between presentation of a subset ofarms designated by the experimenter (e.g., 5 arms available and 3 armsblocked) and completion of the eight-arm win-shift task (i.e., with alleight arms available).

In the habituation phase, rats were familiarized to the maze for an8-minute session on four consecutive days. In each of these sessionsfood rewards were scattered on the RAM, initially on the center platformand arms and then progressively confined to the arms. After thishabituation phase, a standard training protocol was used, in which afood pellet was located at the end of each arm. Rats received one trialeach day for 18 days. Each daily trial terminated when all eight foodpellets had been obtained or when either 16 choices were made or 15minutes had elapsed. After completion of this training phase, a secondtraining phase was carried out in which the memory demand was increasedby imposing a brief delay during the trial. At the beginning of eachtrial, three arms of the eight-arm maze were blocked. Rats were allowedto obtain food on the five arms to which access was permitted duringthis initial ‘information phase’ of the trial. Rats were then removedfrom the maze for 60 seconds, during which time the barriers on the mazewere removed, thus allowing access to all eight arms. Rats were thenplaced back onto the center platform and allowed to obtain the remainingfood rewards during this ‘retention test’ phase of the trial. Theidentity and configuration of the blocked arms varied across trials.

The number of “errors” the AI rats made during the retention test phasewas tracked. An error occurred in the trial if the rats entered an armfrom which food had already been retrieved in the pre-delay component ofthe trial, or if it re-visited an arm in the post-delay session that hadalready been visited.

After completion of the pre-training test, rats were subjected to trialswith more extended delay intervals, i.e., a one-hour delay, between theinformation phase (presentation with some blocked arms) and theretention test (presentation of all arms). During the delay interval,rats remained off to the side of the maze in the testing room, on cartsin their individual home cages. AI rats were pretreated 30-40 minutesbefore daily trials with a one-time shot of the following sixconditions: 1) vehicle control (0.9% saline solution); 2) levetiracetam(1.25 mg/kg/day); 3) levetiracetam (2.5 mg/kg/day); 4) levetiracetam (5mg/kg/day); 5) levetiracetam (10 mg/kg/day); 6) levetiracetam (20mg/kg/day); through intraperitoneal (i.p.) injection. Injections weregiven every other day with intervening washout days. Each AI rat wastreated with all six conditions within 23 days of testing. Tocounterbalance any potential bias, drug effect was assessed usingascending-descending dose series, i.e., the dose series was given firstin an ascending order and then repeated in a descending order.Therefore, each dose had two determinations.

Parametric statistics (paired t-tests) was used to compare the retentiontest performance of the AI rats in the one-hour delay version of the RAMtask in the context of different doses of levetiracetam and vehiclecontrol (see FIG. 3). The average numbers of errors that occurred in thetrials were also significantly fewer with levetiracetam treatment of 5mg/kg/day (average no. of errors±standard error of the mean(SEM)=0.75±0.32) and 10 mg/kg/day (average no. of errors±SEM=0.80±0.27)than using vehicle control (average no. of errors±SEM=2.00±0.42).Relative to vehicle control treatment, levetiracetam significantlyimproved memory performance at 5 mg/kg/day (t(9)=2.18, p=0.057) and 10mg/kg/day (t(9)=2.37, p=0.042).

The radial arm maze task was also used to evaluate the effect of acombination therapy with Levetiracetam (i.p. administration) andvalproate (subcutaneous administration). Levetiracetam, on its own, waseffective in reducing the number of errors by AI rats in the radial armmaze at 5-10 mg/kg doses, but not at 1.25 mg/kg or 2.5 mg/kg. Valproate,on its own, was effective at 100 mg/kg but not at 25 mg/kg or 50 mg/kg.See FIG. 4. Combining the two drugs, however, had a synergistic effect.A combined administration of 50 mg/kg valproate with 2.5 mg/kglevetiracetam, neither being an effective dose when administeredindividually, resulted in a reduced number of errors in the radial armmaze task. This result was also obtained at an even lower dose of 1.25mg/kg levetiracetam combined with 50 mg/kg valproate. See FIG. 5. Anisobologram of levetiracetam and valproate dosages confirmed that theeffect of the combined 50 mg/kg valproate and 1.25 mg/kg levetivacetam(VPA 50+LEV 1.25; empty circle) had a synergistic (super-additive)effect. The combined 50 mg/kg valproate and 2.5 mg/kg levetivacetam (VPA50+LEV 2.5; dark circle), on the other hand, had a simple additiveeffect, as indicated by its placement on the line. See FIG. 6.

To calculate the human equivalent dose (HED) for levetiracetam dosagefor treatment of age-dependent cognitive impairment in humans, weemployed the formula HED (mg/kg)=rat dose (mg/kg)×0.16 (see Estimatingthe Safe Starting Dose in Clinical Trials for Therapeutics in AdultHealthy Volunteers, December 2002, Center for Biologics Evaluation andResearch). Therefore, the dosage of 5 mg/kg/day in rats is equivalent to0.8 mg/kg/day in humans and the dosage of 10 mg/kg/day in rats isequivalent to 1.6 mg/kg/day in humans.

Example 3: Effect of Levetiracetam in Human Subjects with aMCI

A within-subjects trial of 8 weeks duration, involving 17 amnestic MCI(aMCI) subjects and 17 age-matched controls with a low dose treatment oflevetiracetam is conducted. During the course of the study, each aMCIsubject receives both drug and placebo treatments separately in twoperiods of two weeks each, with the order of treatments among differentaMCI subjects counterbalanced (see FIG. 7). Age-matched control subjectstreated with placebo serve as a further control. Cognitive testing andfMRI imaging data are obtained from the subjects after each two weekperiod of drug/placebo treatment.

Participants and Clinical Characterization

17 right-handed aMCI patients are recruited from the Alzheimer's DiseaseResearch Center (ADRC) at the Johns Hopkins Hospital and otherreferrals. An additional 17 right-handed healthy volunteers arerecruited from the pool of control participants in the ADRC and otherreferrals. All participants are administered the Telephone Interview ofCognitive Status to determine if they are likely to pass the entrycriteria of the study (including criteria for MRI scanning). Allparticipants further undergo neurological, psychiatric, andneuropsychological examination using standardized instruments andmethods. The psychiatric evaluation includes administration of theStructured Clinical Interview for DSM-IV Axis I Disorders and theClinical Dementia Rating (CDR) scale. All aMCI patients have CDR scoresof 0.5. Diagnosis of aMCI is based on the criteria proposed by Petersenet al. (e.g., “Mild cognitive impairment: Aging to Alzheimer's Disease,”Oxford University Press, N.Y. (2003), which include a memory complaint(corroborated by an informant), impaired memory function on testing (1.5standard deviations below norm), otherwise preserved cognitivefunctioning (within 1 standard deviation of norm), no decline infunctional ability, and no dementia. Final aMCI diagnoses are reached byclinical consensus. Exclusion criteria include major neurological orpsychiatric disorders, head trauma with loss of consciousness, historyof drug abuse or dependency, and general contraindications to an MRIexamination (e.g. cardiac pacemaker, aneurysm coils, claustrophobia).Each aMCI subject is required to have a study partner (i.e., aninformant) who can provide information about the subject's dailyfunction and assure that medications are taken appropriately. See FIGS.18A and 18B.

Study Visits:

The study consists of 4 visits over the course of 8 weeks (see FIG. 7).The Baseline Visit is for the purpose of performing medical,neurological, psychiatric, and neurocognitive assessments. Visits 1 and2 are identical to the Baseline Visit but include a fMRI session. TheWashout Visit, at the end of a 4 week washout period, is for the purposeof a brief clinical assessment and initiation of the second drug/placebophase.

Baseline Visit:

At the screening visit, informed consent is obtained from the subject(and an informant in the case of MCI subjects). The subject and theinformant participate in a standardized clinical interview that is usedto determine the degree of the subject's functional impairment in dailylife, based on the Clinical Dementia Rating (CDR) scale. The subject'smedical, neurological, and psychiatric history is obtained (including areview of current medications), as well as the family history ofdementia. Brief medical, neurological and psychiatric exams areconducted (including vital signs). Blood is drawn in order to performstandard laboratory tests needed to determine if the subject meets theentry criteria. The subject is re-screened for contraindications to MRIscanning, using the standard form employed at the Kirby Imaging Center.Brief cognitive testing is performed (described in section onneuropsychological assessment below). These assessments are used todetermine if the subject meets the entry criteria. All of the foregoingare completed using standardized forms. If the subject meets entrycriteria for the study, the subject is given the study medication (drugor placebo, randomly selected), and instructions about how it should betaken. The subject is advised about the potential for having suicidalthoughts and advised to stop taking the medication and immediatelycontact the study physician if this occurs.

Visit 1:

At the end of the first drug/placebo period 2 weeks after the BaselineVisit, the medical, neurological and psychiatric evaluations andcognitive testing are repeated. The subject is also clinically evaluatedfor suicidal ideation. Blood is drawn again to repeat the standard testsand to determine whether there are any changes related to drugtreatment; the subject's blood levetiracetam level is also obtained. Allmedication dispensed at the Baseline Visit (drug or placebo) iscollected and subject compliance with the medication regimen isassessed. The first fMRI session (with cognitive tests) is conducted onthe same day, either immediately before or immediately after theclinical assessment. Subjects discontinue first period treatment at thisvisit.

Washout Visit:

At the end of a washout period (4 weeks) following Visit 1, the subjectreceives a brief medical screening, including a medical and psychiatricevaluation. Blood is drawn to obtain the blood levetiracetam level (toconfirm washout). The subject is provided with new medication (drug orplacebo, alternated from what was assigned in the previous treatmentperiod) for the final phase of the study with instructions about how itshould be taken.

Visit 2:

At approximately 2 weeks after the Washout Visit (i.e., 2 weeks afterstarting the second treatment period), the medical, neurological andpsychiatric evaluations and the cognitive testing are repeated. Thesubject is clinically evaluated for suicidal ideation. Blood is drawnagain to repeat the standard tests and to determine whether there wereany changes related to drug treatment; the subject's blood levetiracetamlevel is also obtained. All medication dispensed at the Washout Visit iscollected and subject compliance with the medication regimen isassessed. The second fMRI session (with cognitive tests) is repeated onthe same day, either immediately before or immediately after theclinical assessment.

Neuropsychological Assessment

All participants undergo neuropsychological evaluation at the time ofassessment for treatment efficacy (Visits 1 and 2), as well as at theBaseline Visit. The evaluation occurs outside of the scanner andincludes the Buschke Selective Reminding Test (Buschke and Fuld, 1974)and the Verbal Paired Associates subtest, the Logical Memory subtest,the Visual Reproduction subtest of the Wechsler Memory Scale-Revised(WMS-R) (Wechsler, 1997), and the Benton Visual Retention Test, as thesetasks are particularly sensitive to medial temporal lobe function andearly memory problems (Marquis et al., 2002 and Masur et al., 1994).Additionally, subjects are asked to complete tests of more generalcognitive function such as tests to assess general mental status,executive function, attention and general naming ability. Allneuropsychological tests are administered by a trained researchassistant during a 60-minute session. As the three neuropsychologicalassessments in this study occur within a time period of 8 weeks,different versions of the neuropsychological tests are used to minimizetest specific practice effects. Breaks are provided to the subject asneeded.

Drug Administration

As described above, the drug treatment period is the two weeks precedingVisit 1 or 2 (with the two week period preceding the other Visit beingthe placebo phase). For the subjects receiving the drug treatment, halfa scored 250 mg tablet of levetiracetam is used to achieve a dose of 125mg/kg twice a day, which is approximately 3.6 mg/kg/day (assuming anaverage adult human weight of 70 kg).

All drug and placebo preparations are performed on a 1:1 allocation. Thepharmacy randomize patients as they enroll, and keep a list of drugassignment.

Levetiracetam is rapidly and almost completely absorbed after oraladministration, and its bioavailability is not affected by food. Plasmahalf-life of levetiracetam is approximately 7±1 hour (expected to be9-10 hours in elderly due to decreased renal function). Absorption israpid, with peak plasma concentrations occurring about 1 hour followingoral administration. Steady state can be achieved after 2 days ofmultiple twice-daily dosing.

A typical starting dose of levetiracetam in treating epilepsy in humansis 500 mg twice a day, which is approximately 14.3 mg/kg/day. The dosageis then is increased until optimal efficacy, up to 50 mg/kg/day. Thus,the dose used in this experiment is a quarter of the lowest human doseused for treating epilepsy.

Even lower dosages, e.g., of 25-60 mg twice a day, are contemplated,based on the results of previous animal studies that indicated low-doseefficacy. The highest effective doses of levetiracetam used in theanimal model are 5-10 mg/kg (given acutely). The human equivalent dose(HED), calculated as described above, of this dosage for treatment ofage-dependent cognitive impairment in humans is equivalent to 0.8-1.6mg/kg/day (or 28-56 mg twice a day).

MRI Data Acquisition

Imaging data are obtained through high-resolution methods developed inthe Stark laboratory. Data are collected on a Phillips 3 Tesla scanner(Eindhoven, The Netherlands) equipped with an 8-channel SENSE(Sensitivity Encoding) head coil, located at the F.M. Kirby ResearchCenter for Functional Brain Imaging at the Kennedy Krieger Institute(Baltimore, Md.). High-resolution echo-planar images are collected usingan acquisition matrix of 64×64, a repetition time of 1500 milliseconds,an echo time of 30 milliseconds, a flip angle of 70 degrees, a SENSEfactor of 2, and an isotropic resolution of 1.5 mm×1.5 mm×1.5 mm with nogap. Nineteen oblique slices are acquired parallel to the principallongitudinal axis of the hippocampus and covered the entire medialtemporal lobe region bilaterally. In addition to the functional runs, awhole-brain MPRAGE structural scan (parameters: 150 oblique slices, 1 mmisotropic resolution) is acquired.

Image Analysis

Data analysis is carried out using the Analysis for FunctionalNeuroimages (AFNI, release 2008_07_18_1710) software. Images are firstco-registered to correct for within- and across-scan head motion.Acquisitions in which a significant motion event occur (more than 3degrees of rotation or 2 mm of translation in any direction relative toprior acquisition), plus and minus one time repetition for 1.5 seconds,are excluded from the analyses. Structural anatomical data areregistered to standard stereotaxic space (Talairach & Tournoux, 1988),and the same parameters are subsequently applied to the functional data.Behavioral vectors are produced to model different trial types.

The ROI-LDDMM (large deformation diffeomorphic metric mapping of theregion of interest) method, a technique for cross-subject alignment,increases the power of multisubject regional fMRI studies by focusingthe alignment power specifically on the ROIs (regions of interest) andnot elsewhere in the brain. First, all subjects' anatomical andfunctional scans are normalized to the Talairach atlas using AFNI.Sub-regions of the medial temporal lobe and the hippocampus (bilateralentorhinal cortex, perirhinal cortex, parahippocampal cortex,CA3/dentate region, CA1 region, and subiculum) are segmented in threedimensions on the MPRAGE scans. The labels for the CA3 region anddentate gyrus (DG) are combined. The anatomically defined ROIs are thenused to calculate the ROI-LDDMM 3D vector field transformation for eachsubject using a customized template based on the mean of the entiresample tested as the target. The ROI-LDDMM transformations for eachindividual subject's ROIs are then applied to the fit coefficient maps.

Group data are analyzed using a two-way Analysis of Variance (ANOVA)with trial types and group as fixed factors, and subject as a randomfactor nested within group. A liberal peak threshold of p<0.05, alongwith a spatial extent threshold of 10 voxels are used to definefunctional ROIs on the overall F statistic. This approach, rather thanusing a direct pair-wise contrast, reduces voxel selection biasesbecause any differences amongst the various conditions allowed for avoxel to be selected. This threshold is then combined with theanatomical segmentations to only include voxels inside the regions ofinterest. This serves to exclude voxels that does not change with any ofthe model's factors, effectively limiting the analysis to voxels showingany changes with task condition or group. Voxels within each functionalROI are collapsed for further analysis.

Cognitive Tests During fMRI Scans at Visits 1 and 2

The activity of the subject's medial temporal lobe is measured byfunctional MRI during the subject's participation in an explicit3-alternative forced choice task, where participants view novel,repeated and similar (“lure”) stimuli. The Psychophysics Toolboxextensions in Matlab 7.0 (The MathWorks, Natick, Mass.) is used forstimulus presentation and behavioral data collection. Stimuli are colorphotographs of common objects. Each participant undergoes a series oftesting runs during the functional imaging sessions, each run consistingof a mix of three types of image pairs: similar pairs, identical pairsand unrelated foils. These image pairs are fully randomized throughoutthe run and presented individually as a series of images (see FIG. 10A).Participants are instructed to make a judgment as to whether each objectseen is new, old or similar. Of critical interest are the participants'responses when presented with the second of the pair of similar objects(the “lure”; see FIG. 10B). The correct identification by the subject oflure stimuli as “similar,” provides behavioral evidence of patternseparation, i.e., the separation of similar experiences into distinctnon-overlapping representations. However, an incorrect identification oflure stimuli as “old” or “new,” indicates a failure of patternseparation. Identification of lure stimuli as “old” indicates that thesubject focused on the similarities between the lure stimulus and theearlier-shown partner image. Identification of the lure stimulus as“new” indicates that the subject failed to recall the earlier-shownpartner image altogether. Each run also contains a number of baselinetrials that use a challenging perceptual discrimination task known toprovide a lower and more-stable estimate of baseline activity in themedial temporal lobe (Stark & Squire, 2001 PNAS; Law et al, 2005).

A survey of the activity level of various subregions in the medialtemporal lobe during the cognitive test, as measured by fMRI, shows thataMCI subjects have hyperactive DG/CA3 regions and a hypoactiveentorhinal cortex during the performance of memory tasks, compared toage-matched control subjects.

We assess the level of activity in DG/CA3 during successful memoryjudgments in control and aMCI subjects. The mean activity is calculatedfrom the average activity, as measured by fMRI, during the presentationof lure stimuli correctly identified by subject as “similar” that iscalibrated for baseline activity. FIG. 8A shows that aMCI patientsexhibit DG/CA3 hyperactivity when making these judgments (p=0.013). FIG.8B, however, shows that treatment with levetiracetam reduces DG/CA3hyper-activity in aMCI subjects (p=0.037). The activity level in theaMCI subject treated with the drug, in fact, is normalized to the extentthat that it is statistically indistinguishable from the activity ofcontrol subjects treated with placebo. See FIG. 8C for the mean activityvalues shown in FIGS. 8A and 8B.

The activity level during successful memory judgments in EC issignificantly lower in placebo-treated aMCI subjects compared tocontrols (p=0.003). See FIG. 9A. However, levetiracetam treatmentnormalizes activity in aMCI subjects in EC as well. See FIG. 9B.Levetiracetam treatment increases EC activity during memory judgments inaMCI subjects, such that it is statistically indistinguishable fromplacebo-treated control subjects. See FIG. 9B. See FIG. 9C for the meanactivity values shown in FIGS. 9A and 9B.

The normalization of DG/CA3 and EC activity during memory judgments bylevetiracetam treatment is mirrored in the change seen in the aMCIsubjects' performance in the cognitive task. With placebo treatment,aMCI patients perform worse that control subjects, correctly identifylure items as “similar” less often and incorrectly identifying them as“old” more often (p=0.009). See FIG. 11. However, the performance ofaMCI subjects improves significantly under levetiracetam treatment. SeeFIG. 12. The interaction of more correct “similar” identifications withless incorrect “old” identifications under drug treatment results in asignificant improvement in the performance of this memory task(p=0.039). See FIG. 13 for a table of the data represented in FIGS. 11and 12.

The performance of control-placebo subjects and aMCI subjects with drugor placebo treatment is also compared in other common cognitive tests,such as the Buschke Selective Reminding Test—Delayed Recall (FIGS. 14Aand 14B), the Benton Visual Retention Test (FIGS. 15A and 15B), VerbalPaired Associates Test—Recognition (FIGS. 16A and 16B) and Verbal PairedAssociates Test—Delayed Recall (FIGS. 17A and 17B). In all of thesetests, aMCI subjects treated with placebo perform worse thanplacebo-treated control subjects, and levetiracetam treatment fail torescue performance in aMCI subjects.

There are a number of possible reasons why levetiracetam treatment doesnot help aMCI subjects with performance in these other cognitive tests.The explicit 3-alternative forced choice task done in the fMRI study isa task that is especially sensitive to DG/CA3 function. As such, theperformance of the subjects in this task may be particularly attuned tothe changes in DG/CA3 activity resulting from levetiracetam treatment.Further, the aMCI subjects were treated with levetiracetam for only twoweeks prior to the administration of the cognitive tests. It iscontemplated that a treatment duration of longer than two weeks, e.g.,16 weeks or 8 months, for the drug treatment will result in improvedefficacy. Finally, comparative animal studies (see Example 1) indicatethat an even lower dose would be more effective. The human dosage of 125mg twice a day is equivalent to a rat dosage of 22.3 mg/kg/day. As isshown in Example 2 and FIG. 3, 20 mg/kg levetiracetam is too high a dosein rats, and it fails to improve the performance of AI rats in theradial maze task. The effective doses of levetiracetam used in theanimal model are 5-10 mg/kg. The human equivalent dose (HED) of theoptimal rat dose is 0.8-1.6 mg/kg/day. Such a dosage would result in theadministration of 28-56 mg twice a day (which is substantially lowerthan the 125 mg twice a day used in this study). Thus, it iscontemplated that aMCI subjects will exhibit a further normalization ofDG/CA3 and EC activity, as well as further improved performance incognitive tests, if they are treated with lower doses equivalent to theeffective doses in rat, e.g., 25-60 mg twice a day of levetiracetam.

1. A method for treating schizophrenia or bipolar disorder in a patientin need or at risk thereof, the method comprising the step ofadministering to said subject a therapeutically effective amount of asynaptic vesicle protein 2A (SV2A) inhibitor or a pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof and atherapeutically effective amount of an antipsychotic or apharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrugthereof.
 2. The method of claim 1, wherein the antipsychotic isadministered at a dose that is subtherapeutic as compared to the dose atwhich it is therapeutically effective when administered in the absenceof the SV2A inhibitor.
 3. The method of claim 1, wherein the SV2Ainhibitor is selected from the group consisting of levetiracetam,brivaracetam, and seletracetam and derivatives, analogs,pharmaceutically acceptable salts, hydrates, solvates, polymorphs andprodrugs thereof.
 4. (canceled)
 5. The method of claim 1, wherein theSV2A inhibitor is administered every 12 or 24 hours: a) at a daily doseof 0.001 mg/kg to 5 mg/kg, b) at a daily dose of 0.5 mg/kg to 5 mg/kg;or c) at a daily dose of 0.05 mg/kg to 0.5 mg/kg. 6-7. (canceled)
 8. Themethod of claim 1, wherein the antipsychotic is: a) selected from thegroup consisting of atypical and typical antipsychotics; b) an atypicalantipsychotic; c) selected from the group consisting of aripiprazole,asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone,quetiapine, risperidone and ziprasidone, and pharmaceutically acceptablesalts, hydrates, solvates, polymorphs and prodrugs thereof; d) selectedfrom the group consisting of aripiprazole, olanzapine and ziprasidone,and pharmaceutically acceptable salts, hydrates, solvates, polymorphs,and prodrugs thereof; e) a typical antipsychotic; f) selected from thegroup consisting of acepromazine, benperidol, bromazepam, bromperidol,chlorpromazine, chlorprothixene, clotiapine, cyamemazine, diazepam,dixyrazine, droperidol, flupentixol, fluphenazine, fluspirilene,haloperidol, heptaminol, isopropamide iodide, levomepromazine,levosulpiride, loxapine, melperone, mesoridazine, molindone, oxypertine,oxyprothepine, penfluridol, perazine, periciazine, perphenazine,pimozide, pipamperone, pipotiazine, prochlorperazine, promazine,promethazine, prothipendyl, pyridoxine, sulpiride, sultopride,tetrabenazine, thioproperazine, thioridazine, tiapride, tiotixene,trifluoperazine, triflupromazine, trihexyphenidyl, and zuclopenthixol,and pharmaceutically acceptable salts, hydrates, solvates, polymorphs,and prodrugs thereof; or g) selected from the group consisting ofdopaminergic agents, glutamatergic agents, NMDA receptor positiveallosteric modulators, glycine reuptake inhibitors, glutamate reuptakeinhibitor, metabotropic glutamate receptors (mGluRs) agonists orpositive allosteric modulators (PAMs), glutamate receptor glur5 positiveallosteric modulators (PAMs), M1 muscarinic acetylcholine receptor(mAChR) positive allosteric modulators (PAMs), histamine H3 receptorantagonists, AMPA/kainate receptor antagonists, ampakines (CX-516),glutathione prodrugs, noradrenergic agents, serotonin receptormodulators, cholinergic agents, cannabinoid CB1 antagonists, neurokinin3 antagonists, neurotensin agonists, MAO B inhibitors, PDE10 inhibitors,NNOS inhibits, neurosteroids, and neurotrophic factors. 9-14. (canceled)15. The method of claim 1, wherein the antipsychotic is useful intreating at least one sign or symptom of schizophrenia or bipolardisorder. 16-17. (canceled)
 18. The method of claim 1, wherein the SV2Ainhibitor and the antipsychotic, or their pharmaceutically acceptablesalts, hydrates, solvates, polymorphs, or prodrugs thereof areadministered simultaneously, or sequentially, or in a singleformulation, or in separate formulations. 19-21. (canceled)
 22. Themethod of claim 1, wherein the SV2A inhibitor is selected from the groupconsisting of levetiracetam, brivaracetam, and seletracetam andderivatives, analogs, pharmaceutically acceptable salts, hydrates,solvates, polymorphs and prodrugs thereof and the antipsychotic isselected from the group consisting of aripiprazole, olanzapine andziprasidone, and pharmaceutically acceptable salts, hydrates, solvates,and polymorphs thereof.
 23. The method of claim 1, a) wherein thetreatment has a longer therapeutic effect in the subject than isattained by administering the antipsychotic in the absence of the SV2Ainhibitor by at least about 1.5×, or 2.0×, or 2.5×, or 3.0×, or 3.5×, or4.0×, or 4.5×, or 5.0×, or 5.5×, or 6.0×, or 6.5×, or 7.0×, or 7.5×, or8.0×, or 8.5×, or 9.0×, or 9.5×, or 10×, or greater than about 10×, orb) wherein the treatment has a longer therapeutic effect in the subjectthan is attained by administering the SV2A inhibitor in the absence ofthe antipsychotic by at least about 1.5×, or 2.0×, or 2.5×, or 3.0×, or3.5×, or 4.0×, or 4.5×, or 5.0×, or 5.5×, or 6.0×, or 6.5×, or 7.0×, or7.5×, or 8.0×, or 8.5×, or 9.0×, or 9.5×, or 10×, or greater than about10×.
 24. (canceled)
 25. A method of increasing the therapeutic index ofan antipsychotic or a pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof in a method of treatingschizophrenia or bipolar disorder in a subject in need or at riskthereof, comprising administering an SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof in combination with the antipsychotic or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof to said subject.
 26. The method of claim 25, wherein theincrease in the therapeutic index of the antipsychotic is greater thanthe therapeutic index of the antipsychotic when administered in theabsence of the SV2A inhibitor by at least about 1.5×, or 2.0×, or 2.5×,or 3.0×, or 3.5×, or 4.0×, or 4.5×, or 5.0×, or 5.5×, or 6.0×, or 6.5×,or 7.0×, or 7.5×, or 8.0×, or 8.5×, or 9.0×, or 9.5×, or 10×, or greaterthan about 10×.
 27. The method of claim 25, wherein the SV2A inhibitoris selected from the group consisting of levetiracetam, brivaracetam,and seletracetam, and derivatives, analogs, pharmaceutically acceptablesalts, hydrates, solvates, polymorphs and prodrugs thereof. 28.(canceled)
 29. The method of claim 25, wherein the antipsychotic is: a)selected from the group consisting of atypical and typicalantipsychotics; b) an atypical antipsychotic; c) selected from the groupconsisting of aripiprazole, asenapine, clozapine, iloperidone,olanzapine, lurasidone, paliperidone, quetiapine, risperidone andziprasidone, and pharmaceutically acceptable salts, hydrates, solvates,polymorphs, and prodrugs thereof; d) selected from the group consistingof aripiprazole, olanzapine and ziprasidone, and pharmaceuticallyacceptable salts, hydrates, solvates, and polymorphs thereof; e) atypical antipsychotic; f) selected from the group consisting ofacepromazine, benperidol, bromazepam, bromperidol, chlorpromazine,chlorprothixene, clotiapine, cyamemazine, diazepam, dixyrazine,droperidol, flupentixol, fluphenazine, fluspirilene, haloperidol,heptaminol, isopropamide iodide, levomepromazine, levosulpiride,loxapine, melperone, mesoridazine, molindone, oxypertine, oxyprothepine,penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone,pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl,pyridoxine, sulpiride, sultopride, tetrabenazine, thioproperazine,thioridazine, tiapride, tiotixene, trifluoperazine, triflupromazine,trihexyphenidyl, and zuclopenthixol, and pharmaceutically acceptablesalts, hydrates, solvates, and polymorphs thereof; g) selected from thegroup consisting of dopaminergic agents, glutamatergic agents, NMDAreceptor positive allosteric modulators, glycine reuptake inhibitors,glutamate reuptake inhibitor, metabotropic glutamate receptors (mGluRs)agonists or positive allosteric modulators (PAMs), glutamate receptorglur5 positive allosteric modulators (PAMs), M1 muscarinic acetylcholinereceptor (mAChR) positive allosteric modulators (PAMs), histamine H3receptor antagonists, AMPA/kainate receptor antagonists, ampakines(CX-516), glutathione prodrugs, noradrenergic agents, serotonin receptormodulators, cholinergic agents, cannabinoid CB1 antagonists, neurokinin3 antagonists, neurotensin agonists, MAO B inhibitors, PDE10 inhibitors,NNOS inhibits, neurosteroids, and neurotrophic factors. 30-35.(canceled)
 36. The method of claim 25, wherein the antipsychotic isuseful in treating at least one sign or symptom of schizophrenia orbipolar disorder. 37-38. (canceled)
 39. A pharmaceutical compositioncomprising an SV2A inhibitor and an antipsychotic or theirpharmaceutically acceptable salts, hydrates, solvates, polymorphs orprodrugs.
 40. The pharmaceutical composition of claim 39, wherein theSV2A inhibitor and the antipsychotic or their pharmaceuticallyacceptable salts, hydrates, solvates, polymorphs or prodrugs are inseparate dosage forms or in a unit dosage form.
 41. The composition ofclaim 39, wherein the composition is in a solid form, a liquid form, asuspension form, a sustained release form, a delayed release form, or anextended release form.
 42. The composition of claim 39, wherein the SV2Ainhibitor is selected from the group consisting of levetiracetam,brivaracetam and seletracetam and derivatives, analogs, pharmaceuticallyacceptable salts, hydrates, solvates, polymorphs and prodrugs thereof.43. (canceled)
 44. The composition of claim 39, wherein the SV2Ainhibitor in the composition is present: a) in an amount of 0.07-350 mg;b) in an amount of 50-250 mg; c) in an amount of 3-50 mg; or d) in anamount less than 350 mg, less than 250 mg, less than 200 mg, less than150 mg, less than 100 mg, less than 50 mg, less than 10 mg, less than 5mg, less than 1 mg, less less than 0.5 mg, less than 0.1 mg, or lessthan 0.07 mg. 45-47. (canceled)
 48. The composition of claim 39, whereinthe antipsychotic is: a) selected from the group consisting of atypicaland typical antipsychotics; b) an atypical antipsychotic; c) selectedfrom the group consisting of aripiprazole, asenapine, clozapine,iloperidone, olanzapine, lurasidone, paliperidone, quetiapine,risperidone and ziprasidone, and the pharmaceutically acceptable salts,hydrates, solvates, polymorphs, and prodrugs thereof; d) selected fromthe group consisting of aripiprazole, olanzapine and ziprasidone, andthe pharmaceutically acceptable salts, hydrates, solvates, andpolymorphs thereof; e) a typical antipsychotic; f) selected from thegroup consisting of acepromazine, benperidol, bromazepam, bromperidol,chlorpromazine, chlorprothixene, clotiapine, cyamemazine, diazepam,dixyrazine, droperidol, flupentixol, fluphenazine, fluspirilene,haloperidol, heptaminol, isopropamide iodide, levomepromazine,levosulpiride, loxapine, melperone, mesoridazine, molindone, oxypertine,oxyprothepine, penfluridol, perazine, periciazine, perphenazine,pimozide, pipamperone, pipotiazine, prochlorperazine, promazine,promethazine, prothipendyl, pyridoxine, sulpiride, sultopride,tetrabenazine, thioproperazine, thioridazine, tiapride, tiotixene,trifluoperazine, triflupromazine, trihexyphenidyl, and zuclopenthixol,and the pharmaceutically acceptable salts, hydrates, solvates, andpolymorphs thereof, or g) selected from dopaminergic agents,glutamatergic agents, NMDA receptor positive allosteric modulators,glycine reuptake inhibitors, glutamate reuptake inhibitor, metabotropicglutamate receptors (mGluRs) agonists or positive allosteric modulators(PAMs), glutamate receptor glur5 positive allosteric modulators (PAMs),M1 muscarinic acetylcholine receptor (mAChR) positive allostericmodulators (PAMs), histamine H3 receptor antagonists, AMPA/kainatereceptor antagonists, ampakines (CX-516), glutathione prodrugs,noradrenergic agents, serotonin receptor modulators, cholinergic agents,cannabinoid CB1 antagonists, neurokinin 3 antagonists, neurotensinagonists, MAO B inhibitors, PDE10 inhibitors, NNOS inhibits,neurosteroids, and neurotrophic factors. 49-54. (canceled)
 55. Thecomposition of claim 39, wherein the antipsychotic is useful in treatingat least one sign or symptom of schizophrenia or bipolar disorder.56-57. (canceled)